Stabilized pharmaceutical dosage forms comprising atrasentan

ABSTRACT

The present disclosure relates to: (a) methods of using stabilized pharmaceutical dosage forms comprising atrasentan, or a pharmaceutically acceptable salt thereof, and, optionally, another therapeutic agent to treat type 2 diabetes, microalbuminuria or macroalbuminuria; and (b) methods for the preparation of such pharmaceutical dosage forms.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Non-provisional applicationSer. No. 14/324,603 filed Jul. 7, 2014, and claims priority to U.S.Provisional Application No. 61/843,799 filed Jul. 8, 2013, both of whichare incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure relates to: (a) methods of using stabilizedpharmaceutical dosage forms comprising atrasentan, or a pharmaceuticallyacceptable salt thereof, and, optionally, another therapeutic agent totreat type 2 diabetes, microalbuminuria or macroalbuminuria; and (b)methods for the preparation of such pharmaceutical dosage forms.

BACKGROUND OF THE INVENTION

Atrasentan is a potent and selective antagonist for the endothelin A(ET_(A)) receptor. It previously was evaluated in clinical trials forthe treatment of prostate cancer at daily doses ranging from 2.5 mg toat least 95 mg. Lower daily doses of atrasentan currently are beingevaluated in clinical trials for the treatment of chronic kidney diseaseassociated with Type II diabetes. Although the proprietary atrasentanpharmaceutical dosage forms most recently employed in these clinicaltrials were suitable for such clinical trials, they did not exhibit thelonger-term stability profile needed for a commercial drug product.Accordingly, there is a need for atrasentan pharmaceutical dosage formshaving improved stability profiles that comply with regulatoryrequirements and are suitable for commercial use.

SUMMARY OF THE INVENTION

The present disclosure relates to a method of treating type 2 diabetes,microalbuminuria or macroalbuminuria. The method comprises administeringdaily to a human subject a dosage form comprising:

(a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof; wherein the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthe dosage form is from about 0.05 weight percent to about 2.0 weightpercent on an atrasentan free base equivalent weight basis;

(b) a pharmaceutically acceptable anti-oxidant; wherein the molar ratioof the anti-oxidant to atrasentan, or pharmaceutically acceptable saltthereof, is from about 10:1 to about 1:10; and

(c) a pharmaceutically acceptable diluent,

wherein the human subject is susceptible to, or is suffering from, type2 diabetes, microalbuminuria or macroalbuminuria.

The present disclosure relates to a method of preparing a stablepharmaceutical dosage form. The method comprises:

(a) combining atrasentan, or a pharmaceutically acceptable salt thereof,with a pharmaceutically acceptable polymeric binder to form a firstmixture;

(b) blending the first mixture with a pharmaceutically acceptablediluent and a pharmaceutically acceptable anti-oxidant to form a secondmixture; and

(c) encapsulating or tableting the second mixture to yield the dosageform, wherein the molar ratio of the anti-oxidant to atrasentan, orpharmaceutically acceptable salt thereof, is from about 10:1 to about1:10.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.”

The term “atrasentan” refers to the compound(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylicacid which has the structure shown below:

The term “atrasentan, or a pharmaceutically acceptable salt thereof” asused throughout this disclosure is intended to encompass the free baseform of the compound shown above as well as any pharmaceuticallyacceptable salt of the compound, such as a hydrochloride salt. Unlessotherwise stated, any reference to an amount of atrasentan in thisdisclosure is based on the free base equivalent weight of atrasentan.For example, 0.75 mg of atrasentan refers to 0.75 mg of atrasentan inthe free base form or an equivalent amount of a salt form of atrasentan.Methods for making atrasentan are described, for example, in U.S. Pat.Nos. 5,731,434; 5,622,971; 5,767,144; 6,162,927; 6,380,241; 6,462,194;6,946,481; 7,208,517; and 7,365,093. The contents of these patents areincorporated by reference in this application.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicants intend each of those words to be sointerpreted in construing this patent, including the claims below.

The term “pharmaceutically acceptable” (such as in the recitation of a“pharmaceutically acceptable salt” or a “pharmaceutically acceptablediluent”) refers to a material that is compatible with administration toa subject, e.g, the material does not cause an undesirable biologicaleffect. Examples of pharmaceutically acceptable salts are described in“Handbook of Pharmaceutical Salts: Properties, Selection, and Use” byStahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Examples ofpharmaceutically acceptable excipients are described in the “Handbook ofPharmaceutical Excipients,” Rowe et al., Ed. (Pharmaceutical Press,7^(th) Ed., 2012).

The term “subject” refers to an animal. In one aspect, the animal is amammal, including a human or non-human, preferably a human subject.

The terms “treating” and “treatment” refer to ameliorating, suppressing,eradicating, reducing the severity of, decreasing the frequency ofincidence of, preventing, reducing the risk of, or delaying the onset ofthe condition.

The abbreviation “HDPE” refers to high-density polyethylene.

The abbreviation “HPMC” refers to hydroxypropyl methylcellulose.

The abbreviation “UACR” refers to urinary-albumin-to-creatine ratio.

II. Stabilized Solid Dosage Forms

The present disclosure relates to stable solid pharmaceutical dosageforms comprising atrasentan, or a pharmaceutically acceptable saltthereof. Among the challenges in developing such dosage forms are thelow atrasentan dose required for the dosage form, the narrow therapeuticwindow for treating patients, the inherent chemical instability ofatrasentan in the presence of moisture and many common excipients, andthe safe handling requirements due to the potency of atrasentan. Thestabilized solid dosage forms of the present disclosure, however,overcome such challenges and allow for the use of a broader range ofexcipients (e.g., metal-ion containing excipients such as magnesiumstearate), packaging configurations (e.g., blister packs), andmanufacturing conditions (e.g., wet granulation).

The low dosing and the narrow therapeutic window for atrasentan havebeen confirmed through analysis of the data collected from recent PhaseIIb clinical trials in subjects with diabetic nephropathy. These PhaseIIb clinical trials evaluated the safety and efficacy of atrasentan toidentify an appropriate balance between the systemic effects ofatrasentan (which can lead to adverse side effects such as edema) andthe efficacy effects of atrasentan. Analysis of the clinical dataresulted in a finding that for the subjects tested a daily dose ofatrasentan less than about 0.25 mg generally was sub-therapeutic while adaily dose greater than about 1.25 mg generally resulted in an increasein adverse effects, particularly peripheral edema, without any furtherimprovement in efficacy relative to the 1.25 mg daily dose. Within thisnarrow therapeutic window (about 0.25 mg to about 1.25 mg daily),atrasentan was found to significantly reduce residual albuminuria andthe urinary-albumin-to-creatine ratio in the subjects studied. Reductionof residual albuminuria and the urinary-albumin-to-creatine ratio aresurrogate endpoints generally associated with delaying the progressionof end-stage renal disease and associated cardiovascular complications.

As noted above, atrasentan will degrade in the presence of many commonexcipients. It is believed that hydrolysis, particularly acid-catalyzedhydrolysis, and oxidation are the primary degradation pathways foratrasentan in low-dose, non-stabilized solid dosage forms. It is furtherbelieved that the primary degradation products of atrasentan inlow-dose, non-stabilized solid dosage forms are the diol, pyrrolidineacid, and N-oxide shown below:

The diol and pyrrolidine acid are believed to form throughacid-catalyzed hydrolysis while the N-oxide is believed to form throughan oxidative mechanism. Degradation of atrasentan generally isexacerbated as acidity, moisture content, and metal ion content (such asNa⁺, Mg²⁺, and Ca²⁺) increase in the dosage form or in the specificcomponents of the dosage form. The incompatibility of atrasentan withmetal ions is believed to be due to the metal ions catalyzing anoxidation reaction and/or forming a complex with atrasentan.

The low dosing, potent nature, and chemical instability of atrasentanfurther increase the difficulty of developing a suitable process for thepreparation of the dosage form. A suitable process generally willensure, inter alia, that atrasentan can be safely handled during thepreparation of the dosage form and that dose-to-dose content uniformitycan be maintained. One potential approach is to dissolve or disperse theatrasentan in a liquid vehicle (such as water) during processing tominimize the generation of airborne dust and the associated risk ofoperator exposure to the drug. Dissolving or dispersing the atrasentanin a liquid vehicle during processing also can assist with maintainingsuitable dose-to-dose content uniformity for the dosage form. Thechemical instability of atrasentan in the presence of water coupled withthe decreased chemical stability normally associated with solution statechemistry, however, raises potential concerns that use of a processemploying a liquid vehicle to prepare the atrasentan dosage form (suchas a process comprising a wet granulation step in which atrasentan iswet granulated with the other excipients during the preparation of thedosage form) may not result in an acceptable final dosage form.

Applicants have discovered stable solid pharmaceutical dosage formscomprising atrasentan, or a pharmaceutically acceptable salt thereof,that overcome these challenges. In general, the dosage forms comprise astabilizing amount of an anti-oxidant; a stabilizing amount of apolymeric binder; or a first amount of an anti-oxidant and a secondamount of a polymeric binder wherein the first amount and the secondamount together provide a stabilizing effect. In one aspect, the dosageform comprises a stabilizing amount of L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof. In another aspect, the dosage formcomprises a stabilizing amount of a polymeric binder selected from thegroup consisting of hydroxymethylpropylcellulose,hydroxyethyl-propylcellulose, and hydroxypropylellulose. In anotheraspect, the dosage form comprises a stabilizing amount ofhydroxymethylpropylcellulose. In another aspect, the dosage formcomprises a first amount of L-cysteine, or a pharmaceutically acceptablesalt or ester thereof; a second amount of a polymeric binder selectedfrom the group consisting of hydroxymethylpropylcellulose,hydroxyethylpropylcellulose, and hydroxypropylellulose; and the firstamount and the second amount together provide a stabilizing effect. Inanother aspect, the dosage form comprises a first amount of L-cysteine,or a pharmaceutically acceptable salt or ester thereof; a second amountof a hydroxymethylpropyl-cellulose; and the first amount and the secondamount together provide a stabilizing effect. In further aspects, theprocess for preparing the dosage form comprises a wet granulation stepwherein a liquid mixture comprising the atrasentan, or apharmaceutically acceptable salt thereof, and the polymeric binder isprepared and used as a granulating agent during the wet granulationstep.

A. Dosage Forms Comprising an Anti-Oxidant

In one embodiment, the disclosure relates to a stable solidpharmaceutical dosage form comprising:

(a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof; wherein the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthe dosage form is from about 0.05 weight percent to about 2.0 weightpercent on an atrasentan free base equivalent weight basis;

(b) a pharmaceutically acceptable anti-oxidant; wherein the molar ratioof the anti-oxidant to atrasentan, or pharmaceutically acceptable saltthereof, is from about 10:1 to about 1:10; and

(c) a pharmaceutically acceptable diluent;

wherein degradation of atrasentan in the dosage form is less thandegradation of atrasentan in an otherwise identical dosage form lackingthe anti-oxidant when the dosage forms are stored for a storage periodof six months at about 40° C. and about 75% relative humidity.

In one embodiment, the dosage form is stored during the storage periodin a semi-permeable container or a substantially impermeable container.In one aspect, the dosage form is stored during the storage period in asealed HDPE bottle or a blister package. In another aspect, the dosageform is stored during the storage period in a sealed HDPE bottle. Inanother aspect, the dosage form is stored during the storage period in ablister package.

(i) Atrasentan

The dosage form can comprise a free base of atrasentan, apharmaceutically acceptable salt of atrasentan, or a combinationthereof. In one aspect, the dosage form comprises a free base ofatrasentan. In another aspect, the dosage form comprises apharmaceutically acceptable salt of atrasentan. In another aspect, thedosage form comprises a hydrochloride salt of atrasentan.

In one embodiment, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in the dosage form is from about 0.1 weightpercent to about 2.0 weight percent on an atrasentan free baseequivalent weight basis. In one aspect, the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in the dosageform is from about 0.2 weight percent to about 1.0 weight percent on anatrasentan free base equivalent weight basis. In another aspect, theweight percent of atrasentan, or pharmaceutically acceptable saltthereof, in the dosage form is from about 0.3 weight percent to about0.8 weight percent on an atrasentan free base equivalent weight basis.In another aspect, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in the dosage form is from about 0.40 weightpercent to about 0.45 weight percent on an atrasentan free baseequivalent weight basis. In another aspect, the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in the dosageform is from about 0.60 weight percent to about 0.65 weight percent onan atrasentan free base equivalent weight basis.

In another embodiment, the dosage form comprises from about 0.40 mg toabout 1.00 mg of atrasentan, or an equivalent amount of apharmaceutically acceptable salt thereof. In one aspect, the dosage formcomprises from about 0.40 mg to about 0.85 mg of atrasentan, or anequivalent amount of a pharmaceutically acceptable salt thereof. Inanother aspect, the dosage form comprises about 0.50 mg of atrasentan,or an equivalent amount of a pharmaceutically acceptable salt thereof.In another aspect, the dosage form comprises about 0.75 mg ofatrasentan, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

In another embodiment, the dosage form comprises atrasentanhydrochloride. In one aspect, the dosage form comprises atrasentanhydrochloride having a solid-state form selected from the groupconsisting of amorphous atrasentan hydrochloride, atrasentanhydrochloride Form I, atrasentan hydrochloride Form II, and atrasentanhydrochloride Form III. In another aspect, the dosage form comprisesamorphous atrasentan hydrochloride. The properties and preparation ofamorphous atrasentan hydrochloride are discussed in greater detail in WO2006/034085. In another aspect, the dosage form comprises atrasentanhydrochloride Form I. The properties and preparation of atrasentanhydrochloride Form I are discussed in greater detail in WO 2006/034094.In another aspect, the dosage form comprises atrasentan hydrochlorideForm II. The properties and preparation of atrasentan hydrochloride FormII are discussed in greater detail in WO 2006/034084. In another aspect,the dosage form comprises atrasentan hydrochloride Form III. Theproperties and preparation of atrasentan hydrochloride Form III arediscussed in greater detail in WO 2006/034234. The contents of thesepatent applications are incorporated by reference in this application.

(ii) Anti-Oxidant

Suitable anti-oxidants for use in the disclosed dosage forms includeanti-oxidants that function as reducing agents and are oxidized topharmaceutically acceptable reduced products in the dosage form. In oneembodiment, the anti-oxidant has an oxidation reduction potential lessthan the oxidation reduction potential of atrasentan (i.e., an oxidationreduction potential less than about 900 mV) and greater than about 550mV. In one aspect, the anti-oxidant has an oxidation reduction potentialless than about 550 mV. In another aspect, the anti-oxidant has anoxidation reduction potential from about 1 mV to about 550 mV. Inanother aspect, the solubility of the anti-oxidant in water at about 25°C. is greater than about 24 mg/mL. In another aspect, the anti-oxidantis an amino acid, or a pharmaceutically acceptable salt or esterthereof. In another aspect, the anti-oxidant is L-cysteine, or apharmaceutically acceptable salt or ester thereof. In another aspect,the anti-oxidant is selected from the group consisting of L-cysteinehydrochloride monohydrate, L-cysteine hydrochloride anhydrate, andL-cysteine ethyl ester. In another aspect, the dosage form comprisesL-cysteine hydrochloride monohydrate.

In another embodiment, the weight percent of the anti-oxidant in thedosage form is from about 0.05 weight percent to about 1.0 weightpercent. In one aspect, the weight percent of the anti-oxidant in thedosage form is from about 0.07 weight percent to about 0.7 weightpercent. In another aspect, the weight percent of the anti-oxidant inthe dosage form is from about 0.09 weight percent to about 0.5 weightpercent.

In another embodiment, the molar ratio of the anti-oxidant toatrasentan, or pharmaceutically acceptable salt thereof, is from about10:1 to about 1:10. In one aspect, the molar ratio of the anti-oxidantto atrasentan, or pharmaceutically acceptable salt thereof, in thedosage form is from about 5:1 to about 1:5. In another aspect, the molarratio of the anti-oxidant to atrasentan, or pharmaceutically acceptablesalt thereof, is from about 2:1 to about 1:2. In another aspect, themolar ratio of the anti-oxidant to atrasentan, or pharmaceuticallyacceptable salt thereof, is about 1:1.

(iii) Diluent

Suitable diluents for use in the disclosed dosage forms include, but arenot limited to, lactose (such as lactose monohydrate, lactose anhydrous,and PHARMATOSE® DCL21), sucrose, glucose, mannitol, sorbitol, isomalt,microcrystalline cellulose (such as AVICEL® PH101 and AVICEL® PH102),silicified microcrystalline cellulose (such as PROSOLV® SMCC 50 and SMCC90), dicalcium phosphate, starches, and combinations thereof. In oneaspect, the diluent is selected from the group consisting of lactose,mannitol, isomalt, microcrystalline cellulose, dicalcium phosphate, andcombinations thereof. In another aspect, the diluent is lactose.

In one embodiment, the weight percent of the diluent in the dosage formis from about 70 weight percent to about 99 weight percent. In oneaspect, the weight percent of the diluent in the dosage form is fromabout 80 weight percent to about 99 weight percent. In another aspect,the weight percent of the diluent in the dosage form is from about 85weight percent to about 99 weight percent.

(iv) Binder

In one embodiment, the dosage form further comprises a pharmaceuticallyacceptable binder. Suitable binders for use in the disclosed dosageforms include, but are not limited to, celluloses, such as hydroxypropylmethylcellulose (e.g., Hypromellose E5 (Premium LV)), hydroxypropylethylcellulose, and hydroxypropyl cellulose, and other pharmaceuticallyacceptable substances with cohesive properties. In one aspect, thebinder is selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose. In another aspect, the binder is hydroxypropylmethylcellulose. In another aspect, the binder ishydroxypropylcellulose. In another aspect, the binder ishydroxyethylpropylcellulose.

In another embodiment, the dosage form further comprises apharmaceutically acceptable binder and the weight percent of the binderin the dosage form is from about 1.0 weight percent to about 10.0 weightpercent. In one aspect, the weight percent of the binder in the dosageform is from about 1.0 weight percent to about 8.0 weight percent. Inanother aspect, the weight percent of the binder in the dosage form isfrom about 1.0 weight percent to about 5.0 weight percent.

In another embodiment, the dosage form further comprises apharmaceutically acceptable binder and the weight to weight ratio of thebinder to atrasentan, or pharmaceutically acceptable salt thereof, isfrom about 2:1 to about 25:1 on an atrasentan free base equivalentweight basis. In one aspect, the weight to weight ratio of the binder tothe atrasentan, or pharmaceutically acceptable salt thereof, is fromabout 1:1 to about 20:1 on an atrasentan free base equivalent weightbasis. In another aspect, the weight to weight ratio of the binder tothe atrasentan, or pharmaceutically acceptable salt thereof, is fromabout 1:1 to about 15:1 on an atrasentan free base equivalent weightbasis.

(v) Disintegrant

In another embodiment, the dosage form optionally comprises apharmaceutically acceptable disintegrant. Suitable disintegrants for usein the disclosed dosage forms include, but are not limited to,cross-linked polyvinyl pyrrolidone (such as POLYPLASDONE™ XL), cornstarch, potato starch, maize starch and modified starches (includingsodium starch glycolate), agar-agar, alginic acids, microcrystallinecellulose, sodium croscarmellose, and combinations thereof. In oneaspect, the disintegrant is selected from the group consisting ofcrospovidone, sodium starch glycolate, and sodium croscarmellose. Inanother aspect, the disintegrant is a cross-linked polyvinylpyrrolidone. In another aspect, the disintegrant is crospovidone.

In another embodiment, the dosage form further comprises apharmaceutically acceptable disintegrant and the weight percent of thedisintegrant in the dosage form is from about 1.0 weight percent toabout 10.0 weight percent. In one aspect, the weight percent of thedisintegrant in the dosage form is from about 1.0 weight percent toabout 6.0 weight percent. In another aspect, the weight percent of thedisintegrant in the dosage form is from about 1.0 weight percent toabout 4.0 weight percent.

In another embodiment, the dosage form further comprises apharmaceutically acceptable disintegrant and the weight to weight ratioof the disintegrant to the anti-oxidant is from about 60:1 to about 3:1.In one aspect, the weight to weight ratio of the disintegrant to theanti-oxidant is from about 50:1 to about 4:1. In another aspect, theweight to weight ratio of the disintegrant to the anti-oxidant is fromabout 35:1 to about 5:1.

(vi) Additional Excipients

In further embodiments, the dosage form optionally comprises apharmaceutically acceptable lubricant and/or glidant. Suitablelubricants and glidants for use in the disclosed dosage forms include,but are not limited to, silicon dioxide (such as SYLOID® 244FP andAEROSIL® 200), glyceryl behenate (such as COMPRITOL®), talc, stearicacid, solid polyethylene glycols, silica gel and mixtures thereof andother substances with lubricating or gliding properties. In one aspect,the lubricant is glyceryl behenate (such as COMPRITOL®). In anotheraspect, the glidant is silicon dioxide (such as SYLOID® 244FP). Inanother aspect, the lubricant is glyceryl behenate and the glidant issilicon dioxide.

In another embodiment, the dosage form further comprises apharmaceutically acceptable glidant. In one aspect, the weight percentof the glidant in the dosage form is from about 0.1 weight percent toabout 1.5 weight percent. In another aspect, the weight percent of theglidant in the dosage form is from about 0.1 weight percent to about 1.0weight percent. In another aspect, the weight percent of the glidant inthe dosage form is from about 0.1 weight percent to about 0.8 weightpercent.

In another embodiment, the dosage form further comprises apharmaceutically acceptable lubricant. In one aspect, the dosage formfurther comprises a pharmaceutically acceptable, hydrophobic lubricant.In another aspect, the weight percent of the lubricant in the dosageform is from about 0.05 weight percent to about 5.0 weight percent. Inanother aspect, the weight percent of the lubricant in the dosage formis from about 0.2 weight percent to about 3.0 weight percent. In anotheraspect, the weight percent of the lubricant in the dosage form is fromabout 0.5 weight percent to about 2.0 weight percent.

In another embodiment, the dosage form further comprises a disintegrant,a glidant, and a lubricant.

(vii) Additional Embodiments

In one embodiment, the molar ratio of the anti-oxidant to atrasentan, orpharmaceutically acceptable salt thereof, is from about 5:1 to about1:5; and the weight to weight ratio of the binder to atrasentan, orpharmaceutically acceptable salt thereof, is from about 1:1 to about20:1 on an atrasentan free base equivalent weight basis. In one aspect,this dosage form further comprises a disintegrant and the weight toweight ratio of the disintegrant to the anti-oxidant is from about 60:1to about 3:1. In another aspect, this dosage form comprises from about0.40 mg to about 0.85 mg of atrasentan, or an equivalent amount of apharmaceutically acceptable salt thereof.

In another embodiment, the molar ratio of the anti-oxidant toatrasentan, or pharmaceutically acceptable salt thereof, is from about2:1 to about 1:2; and the weight to weight ratio of the binder toatrasentan, or pharmaceutically acceptable salt thereof, is from about1:1 to about 15:1 on an atrasentan free base equivalent weight basis. Inone aspect, the dosage form further comprises a disintegrant and theweight to weight ratio of the disintegrant to the anti-oxidant is fromabout 50:1 to about 4:1. In another aspect, the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in this dosageform is from about 0.2 weight percent to about 1.0 weight percent on anatrasentan free base equivalent weight basis. In another aspect, thisdosage form comprises from about 0.40 mg to about 0.85 mg of atrasentan,or an equivalent amount of a pharmaceutically acceptable salt thereof.

In another embodiment, the molar ratio of the anti-oxidant toatrasentan, or pharmaceutically acceptable salt thereof, is about 1:1;and the weight to weight ratio of the binder to atrasentan, orpharmaceutically acceptable salt thereof, is from about 1:1 to about15:1 on an atrasentan free base equivalent weight basis. In one aspect,this dosage form further comprises a disintegrant and the weight toweight ratio of the disintegrant to the anti-oxidant is from about 35:1to about 5:1. In another aspect, the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, in this dosage form is fromabout 0.3 weight percent to about 0.8 weight percent on an atrasentanfree base equivalent weight basis. In another aspect, this dosage formcomprises from about 0.40 mg to about 0.85 mg of atrasentan, or anequivalent amount of a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises from about 0.05 weightpercent to about 1.0 weight percent of the anti-oxidant; and from about1.0 weight percent to about 10.0 weight percent of the binder. In oneaspect, this dosage form further comprises a disintegrant and the weightpercent of the disintegrant in the dosage form is from about 1.0 weightpercent to about 10.0 weight percent. In another aspect, the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthis dosage form is from about 0.1 weight percent to about 2.0 weightpercent on an atrasentan free base equivalent weight basis. In anotheraspect, this dosage form comprises from about 0.40 mg to about 0.85 mgof atrasentan, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

In another embodiment, the dosage form comprises from about 0.07 weightpercent to about 0.70 weight percent of the anti-oxidant; and from about1.0 weight percent to about 8.0 weight percent of the binder. In oneaspect, this dosage form further comprises a disintegrant and the weightpercent of the disintegrant in the dosage form is from about 1.0 weightpercent to about 6.0 weight percent. In another aspect, the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthis dosage form is from about 0.2 weight percent to about 1.0 weightpercent on an atrasentan free base equivalent weight basis. In anotheraspect, this dosage form comprises from about 0.40 mg to about 0.85 mgof atrasentan, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

In another embodiment, the dosage form comprises from about 0.09 weightpercent to about 0.80 weight percent of the anti-oxidant; and from about1.0 weight percent to about 5.0 weight percent of the binder. In oneaspect, this dosage form further comprises a disintegrant and the weightpercent of the disintegrant in the dosage form is from about 1.0 weightpercent to about 4.0 weight percent. In another aspect, the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthis dosage form is from about 0.3 weight percent to about 0.8 weightpercent on an atrasentan free base equivalent weight basis. In anotheraspect, this dosage form comprises from about 0.40 mg to about 0.85 mgof atrasentan, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

In another embodiment, the dosage form comprises:

(a) about 0.1 weight percent to about 2.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.05 weight percent to about 1.0 weight percent of theanti-oxidant;

(c) about 75 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 10.0 weight percent of apharmaceutically acceptable binder;

(e) optionally, about 1.0 weight percent to about 10.0 weight percent ofa pharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.5 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 5.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.1 weight percent to about 2.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.05 weight percent to about 1.0 weight percent of theanti-oxidant;

(c) about 75 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 10.0 weight percent of apharmaceutically acceptable binder;

(e) about 1.0 weight percent to about 10.0 weight percent of apharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.5 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 5.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.2 weight percent to about 1.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.07 weight percent to about 0.7 weight percent of theanti-oxidant;

(c) about 82 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 8.0 weight percent of apharmaceutically acceptable binder;

(e) optionally, about 1.0 weight percent to about 6.0 weight percent ofa pharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.0 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 3.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.2 weight percent to about 1.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.07 weight percent to about 0.7 weight percent of theanti-oxidant;

(c) about 82 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 8.0 weight percent of apharmaceutically acceptable binder;

(e) about 1.0 weight percent to about 6.0 weight percent of apharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.0 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 3.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.3 weight percent to about 0.8 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.09 weight percent to about 0.5 weight percent of theanti-oxidant;

(c) about 87 weight percent to about 99 weight percent of apharmaceutically acceptable diluent;

(d) about 1.0 weight percent to about 5.0 weight percent of apharmaceutically acceptable binder;

(e) optionally, about 1.0 weight percent to about 4.0 weight percent ofa pharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 0.75 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 2.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.3 weight percent to about 0.8 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.09 weight percent to about 0.5 weight percent of theanti-oxidant;

(c) about 87 weight percent to about 99 weight percent of apharmaceutically acceptable diluent;

(d) about 1.0 weight percent to about 5.0 weight percent of apharmaceutically acceptable binder;

(e) about 1.0 weight percent to about 4.0 weight percent of apharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 0.75 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 2.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form is a tablet. In one aspect, thetablet has a weight from about 37.5 mg to about 1500 mg. In anotheraspect, the tablet has a weight from about 50 mg to about 750 mg. Inanother aspect, the tablet has a weight from about 50 mg to about 250mg. In another aspect, the tablet has a weight from about 75 mg to about500 mg. In another aspect, the tablet has a weight from about 75 mg toabout 150 mg. In another aspect, the tablet has a weight from about 100mg to about 250 mg. In another aspect, the tablet has a weight fromabout 100 mg to about 230 mg.

In general, the tablet optionally can be surrounded or coated with atleast one non-rate-controlling layer. The non-rate-controlling layer canbe formed as a single layer, coating or membrane or a plurality ofsingle layers, coatings or membranes. The functions of thenon-rate-controlling layer can include, for example, providing furtherstability for the atrasentan, serving as a process aid and/or as acosmetic enhancement for the formulation, and/or acting as a maskingagent to reduce any undesired odor associated with the formulation.

When the dosage form comprises a non-rate-controlling layer, thenon-rate-controlling layer can be made of one or more polymers, as wellas, other ingredients known in the art, such as, but not limited to,plasticizers, pigments/opacifiers, waxes, etc. Examples of polymers thatcan be used include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylalcohol and polyethylene glycol. Examples of plasticizers that can beused include, but are not limited to, polyethylene glycol(s), glycerin,triacetin, triethyl citrate, diethyl phthalate, L-cysteine, and mineraloils. Examples of pigments/opacifiers that can be used include, but arenot limited to, water soluble dyes (for example, sunset yellow,quinoline yellow, erythrosine, and tartrazine), pigments (for example,aluminum lakes, titanium oxides, iron oxides and talc), and naturalproducts (for example, riboflavin, carotenoids, chlorophyll,anthocyanins, and carmine). An example of a wax that can be usedincludes, but is not limited to, a paraffin wax.

In another embodiment, the dosage form is a tablet coated with apharmaceutically acceptable polymer.

In another embodiment, the dosage form is a capsule.

In another embodiment, the dosage form is packaged in a semi-permeablecontainer. In one aspect, the semi-permeable container is a blisterpack.

In another embodiment, the dosage form is packaged in a substantiallyimpermeable container.

In another embodiment, the dosage form is an immediate release dosageform. In one aspect, the dosage form is an immediate release tablet andreleases at least about 85% of the atrasentan, or pharmaceuticallyacceptable salt thereof, within about 45 minutes as determined in an invitro dissolution test conducted using a USP Dissolution Apparatus 2(Paddle Apparatus), a 0.01N hydrochloric acid dissolution medium, and apaddle rotation of 50 RPM. In another aspect, the dosage form is animmediate release tablet and releases at least about 75% of theatrasentan, or pharmaceutically acceptable salt thereof, within about 30minutes.

In another embodiment, the dosage form comprises less than about 1.0weight percent of total impurities resulting from degradation of theatrasentan, or pharmaceutically acceptable salt thereof, after a storageperiod of six months at about 40° C. and about 75% relative humidity. Inone aspect, degradation of the atrasentan, or pharmaceuticallyacceptable salt thereof, is analyzed using high-performance liquidchromatography.

In another embodiment, the dosage form comprises less than about 0.6weight percent of any single impurity resulting from degradation of theatrasentan, or pharmaceutically acceptable salt thereof, after a storageperiod of six months at about 40° C. and about 75% relative humidity. Inone aspect, degradation of the atrasentan, or pharmaceuticallyacceptable salt thereof, is analyzed using high-performance liquidchromatography.

In another embodiment, the dosage form comprises less than about 1.0weight percent of total impurities and less than about 0.6 weightpercent of any single impurity resulting from degradation of theatrasentan, or pharmaceutically acceptable salt thereof, after a storageperiod of six months at about 40° C. and about 75% relative humidity. Inone aspect, degradation of the atrasentan, or pharmaceuticallyacceptable salt thereof, is analyzed using high-performance liquidchromatography.

B. Dosage Forms Comprising L-Cysteine and/or Polymeric Binder

In one embodiment, the disclosure relates to a stable solidpharmaceutical dosage form comprising:

(a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof; wherein the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthe dosage form is from about 0.05 weight percent to about 2.0 weightpercent on an atrasentan free base equivalent weight basis;

(b) L-cysteine, or a pharmaceutically acceptable salt or ester thereof;wherein the molar ratio of the L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof, to atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 10:1 to about 1:10; and

(c) a pharmaceutically acceptable diluent;

wherein degradation of atrasentan in the dosage form is less thandegradation of atrasentan in an otherwise identical dosage form lackingthe L-cysteine, or a pharmaceutically acceptable salt or ester thereof,when the dosage forms are stored for a storage period of six months atabout 40° C. and about 75% relative humidity.

In another embodiment, the disclosure relates to a stable solidpharmaceutical dosage form comprising:

(a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof; wherein the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthe dosage form is from about 0.05 weight percent to about 2.0 weightpercent on an atrasentan free base equivalent weight basis;

(b) a pharmaceutically acceptable polymeric binder selected from thegroup consisting of hydroxymethylpropylcellulose,hydroxyethylpropylcellulose, and hydroxypropylcellulose; wherein theweight to weight ratio of the binder to atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 2:1 to about 25:1 on anatrasentan free base equivalent weight basis; and

(c) a pharmaceutically acceptable diluent;

wherein degradation of atrasentan in the dosage form is less thandegradation of atrasentan in an otherwise identical dosage form lackingthe polymeric binder when the dosage forms are stored for a storageperiod of six months at about 40° C. and about 75% relative humidity.

In another embodiment, the disclosure relates to a stable solidpharmaceutical dosage form comprising:

(a) about 0.25 mg to about 1.25 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof; wherein the weightpercent of atrasentan, or pharmaceutically acceptable salt thereof, inthe dosage form is from about 0.05 weight percent to about 2.0 weightpercent on an atrasentan free base equivalent weight basis;

(b) L-cysteine, or a pharmaceutically acceptable salt or ester thereof;wherein the molar ratio of the L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof, to atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 10:1 to about 1:10;

(c) a pharmaceutically acceptable polymeric binder selected from thegroup consisting of hydroxymethylpropylcellulose,hydroxyethylpropylcellulose, and hydroxypropylcellulose; wherein theweight to weight ratio of the binder to atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 2:1 to about 25:1 on anatrasentan free base equivalent weight basis; and

(d) a pharmaceutically acceptable diluent;

wherein degradation of atrasentan in the dosage form is less thandegradation of atrasentan in an otherwise identical dosage form lackingthe L-cysteine, or a pharmaceutically acceptable salt or ester thereof,and the polymeric binder when the dosage forms are stored for a storageperiod of six months at about 40° C. and about 75% relative humidity.

In additional aspects of each of the above embodiments, the dosage formis stored during the storage period in a semi-permeable container or asubstantially impermeable container. In another aspect, the dosage formis stored during the storage period in a sealed HDPE bottle or a blisterpackage. In another aspect, the dosage form is stored during the storageperiod in a sealed HDPE bottle. In another aspect, the dosage form isstored during the storage period in a blister package.

(i) Atrasentan

The dosage form can comprise a free base of atrasentan, apharmaceutically acceptable salt of atrasentan, or a combinationthereof. In one aspect, the dosage form comprises a free base ofatrasentan. In another aspect, the dosage form comprises apharmaceutically acceptable salt of atrasentan. In another aspect, thedosage form comprises a hydrochloride salt of atrasentan. In anotheraspect, the dosage form comprises atrasentan hydrochloride having asolid-state form selected from the group consisting of amorphousatrasentan hydrochloride, atrasentan hydrochloride Form I, atrasentanhydrochloride Form II, and atrasentan hydrochloride Form III. In anotheraspect, the dosage form comprises amorphous atrasentan hydrochloride.The properties and preparation of amorphous atrasentan hydrochloride arediscussed in greater detail in WO 2006/034085. In another aspect, thedosage form comprises atrasentan hydrochloride Form I. The propertiesand preparation of atrasentan hydrochloride Form I are discussed ingreater detail in WO 2006/034094. In another aspect, the dosage formcomprises atrasentan hydrochloride Form II. The properties andpreparation of atrasentan hydrochloride Form II are discussed in greaterdetail in WO 2006/034084. In another aspect, the dosage form comprisesatrasentan hydrochloride Form III. The properties and preparation ofatrasentan hydrochloride Form III are discussed in greater detail in WO2006/034234.

In another embodiment, the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, in the dosage form is fromabout 0.1 weight percent to about 2.0 weight percent on an atrasentanfree base equivalent weight basis. In one aspect, the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in the dosageform is from about 0.2 weight percent to about 1.0 weight percent on anatrasentan free base equivalent weight basis. In another aspect, theweight percent of atrasentan, or pharmaceutically acceptable saltthereof, in the dosage form is from about 0.3 weight percent to about0.8 weight percent on an atrasentan free base equivalent weight basis.In another aspect, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in the dosage form is from about 0.40 weightpercent to about 0.45 weight percent on an atrasentan free baseequivalent weight basis. In another aspect, the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in the dosageform is from about 0.60 weight percent to about 0.65 weight percent onan atrasentan free base equivalent weight basis.

In another embodiment, the dosage form comprises from about 0.40 mg toabout 1.00 mg of atrasentan, or an equivalent amount of apharmaceutically acceptable salt thereof. In one aspect, the dosage formcomprises from about 0.40 mg to about 0.85 mg of atrasentan, or anequivalent amount of a pharmaceutically acceptable salt thereof. Inanother aspect, the dosage form comprises about 0.50 mg of atrasentan,or an equivalent amount of a pharmaceutically acceptable salt thereof.In another aspect, the dosage form comprises about 0.75 mg ofatrasentan, or an equivalent amount of a pharmaceutically acceptablesalt thereof.

(ii) L-Cysteine

In one embodiment, the weight percent of the L-cysteine, orpharmaceutically acceptable salt or ester thereof, in the dosage form isfrom about 0.05 weight percent to about 1.0 weight percent. In oneaspect, the weight percent of the L-cysteine, or pharmaceuticallyacceptable salt or ester thereof, in the dosage form is from about 0.07weight percent to about 0.7 weight percent. In another aspect, theweight percent of the L-cysteine, or pharmaceutically acceptable salt orester thereof, in the dosage form is from about 0.09 weight percent toabout 0.5 weight percent.

In another embodiment, the molar ratio of the L-cysteine, orpharmaceutically acceptable salt or ester thereof, to atrasentan, orpharmaceutically acceptable salt thereof, in the dosage form is fromabout 10:1 to about 1:10. In another aspect, the molar ratio of theL-cysteine, or pharmaceutically acceptable salt or ester thereof, toatrasentan, or pharmaceutically acceptable salt thereof, in the dosageform is from about 5:1 to about 1:5. In another aspect, the molar ratioof the L-cysteine, or pharmaceutically acceptable salt or ester thereof,to atrasentan, or pharmaceutically acceptable salt thereof, is fromabout 2:1 to about 1:2. In another aspect, the molar ratio of theL-cysteine, or pharmaceutically acceptable salt or ester thereof, toatrasentan, or pharmaceutically acceptable salt thereof, about 1:1.

In another embodiment, the anti-oxidant is selected from the groupconsisting of L-cysteine hydrochloride monohydrate, L-cysteinehydrochloride anhydrate, and L-cysteine ethyl ester. In another aspect,the dosage form comprises L-cysteine hydrochloride monohydrate.

(iii) Diluent

In one embodiment, the weight percent of the diluent in the dosage formis from about 70 weight percent to about 99 weight percent. In oneaspect, the weight percent of the diluent in the dosage form is fromabout 80 weight percent to about 99 weight percent. In another aspect,the weight percent of the diluent in the dosage form is from about 85weight percent to about 99 weight percent. In another aspect, thediluent is selected from the group consisting of lactose, mannitol,isomalt, and combinations thereof. In another aspect, the diluent islactose.

(iv) Binder

In one embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose. In one aspect, the binder is hydroxypropylmethylcellulose. In another aspect, the binder ishydroxyethylpropyl-cellulose. In another aspect, the binder ishydroxypropylcellulose.

In another embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; and the weight percent of the binder in thedosage form is from about 1.0 weight percent to about 10.0 weightpercent. In one aspect, the weight percent of the binder in the dosageform is from about 1.0 weight percent to about 8.0 weight percent. Inanother aspect, the weight percent of the binder in the dosage form isfrom about 1.0 weight percent to about 5.0 weight percent.

In another embodiment, the dosage form further comprises apharmaceutically acceptable polymeric binder selected from the groupconsisting of hydroxymethylpropyl-cellulose,hydroxyethylpropylcellulose, and hydroxypropylcellulose; and the weightto weight ratio of the binder to atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 2:1 to about 25:1 on anatrasentan free base equivalent weight basis. In one aspect, the weightto weight ratio of the binder to the atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 1:1 to about 20:1 on anatrasentan free base equivalent weight basis. In another aspect, theweight to weight ratio of the binder to the atrasentan, orpharmaceutically acceptable salt thereof, is from about 1:1 to about15:1 on an atrasentan free base equivalent weight basis.

(v) Disintegrant

In one embodiment, the dosage form optionally comprises apharmaceutically acceptable disintegrant. Suitable disintegrants for usein the disclosed dosage forms include, but are not limited to,cross-linked polyvinyl pyrrolidone (such as POLYPLASDONE™ XL), cornstarch, potato starch, maize starch and modified starches (includingsodium starch glycolate), agar-agar, alginic acids, microcrystallinecellulose, sodium croscarmellose, and combinations thereof. In oneaspect, the disintegrant is selected from the group consisting ofcrospovidone, sodium starch glycolate, and sodium croscarmellose. Inanother aspect, the disintegrant is a cross-linked polyvinylpyrrolidone. In another aspect, the disintegrant is crospovidone.

In another embodiment, the dosage form further comprises apharmaceutically acceptable disintegrant. In one aspect, the dosage formfurther comprises a pharmaceutically acceptable disintegrant and theweight percent of the disintegrant in the dosage form is from about 1.0weight percent to about 10.0 weight percent. In one aspect, the weightpercent of the disintegrant in the dosage form is from about 1.0 weightpercent to about 6.0 weight percent. In another aspect, the weightpercent of the disintegrant in the dosage form is from about 1.0 weightpercent to about 4.0 weight percent. In another aspect, the disintegrantis crospovidone.

In another embodiment, the dosage form further comprises apharmaceutically acceptable disintegrant and the weight to weight ratioof the disintegrant to the L-cysteine, or pharmaceutically acceptablesalt or ester thereof, is from about 60:1 to about 3:1. In one aspect,the weight to weight ratio of the disintegrant to the L-cysteine, orpharmaceutically acceptable salt or ester thereof, is from about 50:1 toabout 4:1. In another aspect, the weight to weight ratio of thedisintegrant to the L-cysteine, or pharmaceutically acceptable salt orester thereof, is from about 35:1 to about 5:1.

(v) Additional Excipients

In further embodiments, the dosage form optionally comprises apharmaceutically acceptable lubricant and/or glidant. In one aspect, thedosage form further comprises a pharmaceutically acceptable glidant. Inanother aspect, the weight percent of the glidant in the dosage form isfrom about 0.1 weight percent to about 1.5 weight percent. In anotheraspect, the weight percent of the glidant in the dosage form is fromabout 0.1 weight percent to about 1.0 weight percent. In another aspect,the weight percent of the glidant in the dosage form is from about 0.1weight percent to about 0.8 weight percent. In another aspect, theglidant is silicon dioxide.

In another embodiment, the dosage form further comprises apharmaceutically acceptable lubricant. In one aspect, the dosage formfurther comprises a pharmaceutically acceptable, hydrophobic lubricant.In another aspect, the weight percent of the lubricant in the dosageform is from about 0.05 weight percent to about 5.0 weight percent. Inanother aspect, the weight percent of the lubricant in the dosage formis from about 0.2 weight percent to about 3.0 weight percent. In anotheraspect, the weight percent of the lubricant in the dosage form is fromabout 0.5 weight percent to about 2.0 weight percent. In another aspect,the lubricant is glyceryl behenate.

In another embodiment, the dosage form further comprises a disintegrant,a glidant, and a lubricant.

(vi) Additional Embodiments

In one embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; the molar ratio of the L-cysteine, orpharmaceutically acceptable salt or ester thereof, to atrasentan, orpharmaceutically acceptable salt thereof, is from about 5:1 to about1:5; and the weight to weight ratio of the binder to atrasentan, orpharmaceutically acceptable salt thereof, is from about 1:1 to about20:1 on an atrasentan free base equivalent weight basis. In one aspect,this dosage form further comprises a disintegrant and the weight toweight ratio of the disintegrant to the L-cysteine, or pharmaceuticallyacceptable salt or ester thereof, is from about 60:1 to about 3:1. Inanother aspect, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in this dosage form is from about 0.2 weightpercent to about 1.0 weight percent on an atrasentan free baseequivalent weight basis. In another aspect, this dosage form comprisesfrom about 0.40 mg to about 0.85 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; the molar ratio of the L-cysteine, or apharmaceutically acceptable salt or ester thereof, to atrasentan, orpharmaceutically acceptable salt thereof, is from about 2:1 to about1:2; and the weight to weight ratio of the binder to atrasentan, orpharmaceutically acceptable salt thereof, is from about 1:1 to about15:1 on an atrasentan free base equivalent weight basis. In one aspect,the dosage form further comprises a disintegrant and the weight toweight ratio of the disintegrant to the L-cysteine, or apharmaceutically acceptable salt or ester thereof, is from about 50:1 toabout 4:1. In another aspect, the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, in this dosage form is fromabout 0.2 weight percent to about 1.0 weight percent on an atrasentanfree base equivalent weight basis. In another aspect, this dosage formcomprises from about 0.40 mg to about 0.85 mg of atrasentan, or anequivalent amount of a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; the molar ratio of the L-cysteine, orpharmaceutically acceptable salt or ester thereof, to atrasentan, orpharmaceutically acceptable salt thereof, is about 1:1; and the weightto weight ratio of the binder to atrasentan, or pharmaceuticallyacceptable salt thereof, is from about 1:1 to about 15:1 on anatrasentan free base equivalent weight basis. In one aspect, this dosageform further comprises a disintegrant and the weight to weight ratio ofthe disintegrant to the L-cysteine, or pharmaceutically acceptable saltor ester thereof, is from about 35:1 to about 5:1. In another aspect,the weight percent of atrasentan, or pharmaceutically acceptable saltthereof, in this dosage form is from about 0.3 weight percent to about0.8 weight percent on an atrasentan free base equivalent weight basis.In another aspect, this dosage form comprises from about 0.40 mg toabout 0.85 mg of atrasentan, or an equivalent amount of apharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; the dosage form comprises from about 0.05 weightpercent to about 1.0 weight percent of the L-cysteine, orpharmaceutically acceptable salt or ester thereof; and the dosage formcomprises from about 1.0 weight percent to about 10.0 weight percent ofthe binder. In one aspect, this dosage form further comprises adisintegrant and the weight percent of the disintegrant in the dosageform is from about 1.0 weight percent to about 10.0 weight percent. Inanother aspect, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in this dosage form is from about 0.1 weightpercent to about 2.0 weight percent on an atrasentan free baseequivalent weight basis. In another aspect, this dosage form comprisesfrom about 0.40 mg to about 0.85 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; the dosage form comprises from about 0.07 weightpercent to about 0.70 weight percent of the L-cysteine, orpharmaceutically acceptable salt or ester thereof; and the dosage formcomprises from about 1.0 weight percent to about 8.0 weight percent ofthe binder. In one aspect, this dosage form further comprises adisintegrant and the weight percent of the disintegrant in the dosageform is from about 1.0 weight percent to about 6.0 weight percent. Inanother aspect, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in this dosage form is from about 0.2 weightpercent to about 1.0 weight percent on an atrasentan free baseequivalent weight basis. In another aspect, this dosage form comprisesfrom about 0.40 mg to about 0.85 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises a pharmaceuticallyacceptable polymeric binder selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose; the dosage form comprises from about 0.09 weightpercent to about 0.80 weight percent of the L-cysteine, orpharmaceutically acceptable salt or ester thereof; and the dosage formcomprises from about 1.0 weight percent to about 5.0 weight percent ofthe binder. In one aspect, this dosage form further comprises adisintegrant and the weight percent of the disintegrant in the dosageform is from about 1.0 weight percent to about 4.0 weight percent. Inanother aspect, the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in this dosage form is from about 0.3 weightpercent to about 0.8 weight percent on an atrasentan free baseequivalent weight basis. In another aspect, this dosage form comprisesfrom about 0.40 mg to about 0.85 mg of atrasentan, or an equivalentamount of a pharmaceutically acceptable salt thereof.

In another embodiment, the dosage form comprises:

(a) about 0.1 weight percent to about 2.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.05 weight percent to about 1.0 weight percent of theL-cysteine, or pharmaceutically acceptable salt or ester thereof;

(c) about 75 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 10.0 weight percent of the binder;

(e) optionally, about 1.0 weight percent to about 10.0 weight percent ofa pharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.5 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 5.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.1 weight percent to about 2.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.05 weight percent to about 1.0 weight percent of theL-cysteine, or pharmaceutically acceptable salt or ester thereof;

(c) about 75 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 10.0 weight percent of the binder;

(e) about 1.0 weight percent to about 10.0 weight percent of apharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.5 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 5.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.2 weight percent to about 1.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.07 weight percent to about 0.70 weight percent of theL-cysteine, or pharmaceutically acceptable salt or ester thereof;

(c) about 82 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 8.0 weight percent of the binder;

(e) optionally, about 1.0 weight percent to about 6.0 weight percent ofa pharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.0 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 3.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.2 weight percent to about 1.0 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.07 weight percent to about 0.70 weight percent of theL-cysteine, or pharmaceutically acceptable salt or ester thereof;

(c) about 82 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 8.0 weight percent of the binder;

(e) about 1.0 weight percent to about 6.0 weight percent of apharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 1.0 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 3.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.3 weight percent to about 0.8 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.09 weight percent to about 0.50 weight percent of theL-cysteine, or pharmaceutically acceptable salt or ester thereof;

(c) about 87 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 5.0 weight percent of the binder;

(e) optionally, about 1.0 weight percent to about 4.0 weight percent ofa pharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 0.75 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 2.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form comprises:

(a) about 0.3 weight percent to about 0.8 weight percent of atrasentan,or pharmaceutically acceptable salt thereof, on an atrasentan free baseequivalent weight basis;

(b) about 0.09 weight percent to about 0.50 weight percent of theL-cysteine, or pharmaceutically acceptable salt or ester thereof;

(c) about 87 weight percent to about 99 weight percent of the diluent;

(d) about 1.0 weight percent to about 5.0 weight percent of the binder;

(e) about 1.0 weight percent to about 4.0 weight percent of apharmaceutically acceptable disintegrant;

(f) optionally, about 0 weight percent to about 0.75 weight percent of apharmaceutically acceptable glidant; and

(g) optionally, about 0 weight percent to about 2.0 weight percent of apharmaceutically acceptable lubricant;

wherein the cumulative weight percent for all components of the dosageform equals 100 percent.

In another embodiment, the dosage form satisfies one or more of thefollowing conditions:

(a) the diluent is lactose;

(b) the dosage form comprises a pharmaceutically acceptable binder andthe binder is hydroxypropyl methylcellulose;

(c) the dosage form comprises a pharmaceutically acceptable disintegrantand the disintegrant is crospovidone;

(d) the dosage form comprises a pharmaceutically acceptable glidant andthe glidant is silicon dioxide;

(e) the dosage form comprises a pharmaceutically acceptable lubricantand the lubricant is glyceryl behenate.

In another embodiment, the dosage form is a tablet. In one aspect, thetablet has a weight from about 37.5 mg to about 1500 mg. In anotheraspect, the tablet has a weight from about 50 mg to about 750 mg. Inanother aspect, the tablet has a weight from about 50 mg to about 250mg. In another aspect, the tablet has a weight from about 75 mg to about500 mg. In another aspect, the tablet has a weight from about 75 mg toabout 150 mg. In another aspect, the tablet has a weight from about 100mg to about 250 mg. In another aspect, the tablet has a weight fromabout 100 mg to about 230 mg.

In general, the tablet optionally can be surrounded or coated with atleast one non-rate-controlling layer. The non-rate-controlling layer canbe formed as a single layer, coating or membrane or a plurality ofsingle layers, coatings or membranes. The functions of thenon-rate-controlling layer can include, for example, providing furtherstability for the atrasentan, serving as a process aid and/or as acosmetic enhancement for the formulation, and/or acting as a maskingagent to reduce any undesired odor associated with the formulation (suchas the odor commonly associated with L-cysteine).

When the dosage form comprises a non-rate-controlling layer, thenon-rate-controlling layer can be made of one or more polymers, as wellas, other ingredients known in the art, such as, but not limited to,plasticizers, pigments/opacifiers, waxes, etc. Examples of polymers thatcan be used include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylalcohol and polyethylene glycol. Examples of plasticizers that can beused include, but are not limited to, polyethylene glycol(s), glycerin,triacetin, triethyl citrate, diethyl phthalate, L-cysteine, and mineraloils. Examples of pigments/opacifiers that can be used include, but arenot limited to, water soluble dyes (for example, sunset yellow,quinoline yellow, erythrosine, and tartrazine), pigments (for example,aluminum lakes, titanium oxides, iron oxides and talc), and naturalproducts (for example, riboflavin, carotenoids, chlorophyll,anthocyanins, and carmine). An example of a wax that can be usedincludes, but is not limited to, a paraffin wax.

In another embodiment, the dosage form is a tablet coated with apharmaceutically acceptable polymer.

In another embodiment, the dosage form is a capsule.

In another embodiment, the dosage form is packaged in a semi-permeablecontainer. In one aspect, the semi-permeable container is a blisterpack.

In another embodiment, the dosage form is packaged in a substantiallyimpermeable container.

In another embodiment, the dosage form is an immediate release dosageform. In one aspect, the dosage form is an immediate release tablet andreleases at least about 85% of the atrasentan, or pharmaceuticallyacceptable salt thereof, within about 45 minutes as determined in an invitro dissolution test conducted using a USP Dissolution Apparatus 2(Paddle Apparatus), a 0.01N hydrochloric acid dissolution medium, and apaddle rotation of 50 RPM. In another aspect, the dosage form is animmediate release tablet and releases at least about 75% of theatrasentan, or pharmaceutically acceptable salt thereof, within about 30minutes.

In another embodiment, the dosage form comprises less than about 1.0weight percent of total impurities resulting from degradation of theatrasentan, or pharmaceutically acceptable salt thereof, after a storageperiod of six months at about 40° C. and about 75% relative humidity. Inone aspect, degradation of the atrasentan, or pharmaceuticallyacceptable salt thereof, is analyzed using high-performance liquidchromatography.

In another embodiment, the dosage form comprises less than about 0.6weight percent of any single impurity resulting from degradation of theatrasentan, or pharmaceutically acceptable salt thereof, after a storageperiod of six months at about 40° C. and about 75% relative humidity. Inone aspect, degradation of the atrasentan, or pharmaceuticallyacceptable salt thereof, is analyzed using high-performance liquidchromatography.

In another embodiment, the dosage form comprises less than about 1.0weight percent of total impurities and less than about 0.6 weightpercent of any single impurity resulting from degradation of theatrasentan, or pharmaceutically acceptable salt thereof, after a storageperiod of six months at about 40° C. and about 75% relative humidity. Inone aspect, degradation of the atrasentan, or pharmaceuticallyacceptable salt thereof, is analyzed using high-performance liquidchromatography.

III. Methods of Treatment

The present disclosure also relates to methods of treating a conditionin a subject, particularly a human subject suffering from or susceptibleto the condition, comprising administering once daily to the subject astable solid pharmaceutical dosage form comprising atrasentan, or apharmaceutically acceptable salt thereof, as described in any of theembodiments of the disclosure.

In one embodiment, the present disclosure relates to methods of treatingnephropathy in a human subject suffering from or susceptible tonephropathy comprising administering once daily to the subject a stablesolid pharmaceutical dosage form comprising atrasentan, or apharmaceutically acceptable salt thereof, as described in any of theembodiments of the disclosure. In a further aspect, the nephropathytreated is diabetic nephropathy. In a further aspect, the subjectselected for treatment is suffering from diabetic nephropathy. In afurther aspect, the subject selected for treatment is suffering fromtype 2 diabetes mellitus. In a further aspect, the subject selected fortreatment is suffering from one or more of the following conditions: (a)diabetic nephropathy; (b) type 2 diabetes; (c) Stage 3 chronic kidneydisease, Stage 4 chronic kidney disease, or end stage renal disease; (d)a urinary-albumin-to-creatinine ratio greater than about 30 mg/g (i.e.,the subject is suffering from microalbuminuria); (e) aurinary-albumin-to-creatinine ratio greater than about 300 mg/g (i.e.,the subject is suffering from macroalbuminuria); and/or (f) an estimatedglomerular filtration rate from about 25 ml/min/1.73 m² to about 59ml/min/1.73 m². In a further aspect, the subject is also administered asecond therapeutic agent that inhibits one or more elements of therenin-angiotensin-aldosterone system. In a further aspect, the secondtherapeutic agent that inhibits one or more elements of therenin-angiotensin-aldosterone system is selected from the groupconsisting of diuretics, angiotensin converting enzyme inhibitors,angiotensin II receptor blockers, calcium channel blockers, renininhibitors, and aldosterone antagonists. In a further aspect, the secondtherapeutic agent that inhibits one or more elements of therenin-angiotensin-aldosterone system is selected from the groupconsisting of angiotensin converting enzyme inhibitors and angiotensinII receptor blockers.

In another embodiment, the present disclosure relates to methods oftreating chronic kidney disease in a human subject suffering from orsusceptible to chronic kidney disease comprising administering oncedaily to the subject a stable solid pharmaceutical dosage formcomprising atrasentan, or a pharmaceutically acceptable salt thereof, asdescribed in any of the embodiments of the disclosure. In a furtheraspect, the chronic kidney disease is Stage 3 or Stage 4 chronic kidneydisease. In a further aspect, the chronic kidney disease is end stagerenal disease. In a further aspect, the treatment delays progression ofchronic kidney disease in the subject. In a further aspect, thetreatment delays progression of end stage renal disease in the subject.In a further aspect, the subject selected for treatment is sufferingfrom diabetic nephropathy. In a further aspect, the subject selected fortreatment is suffering from type 2 diabetes mellitus. In a furtheraspect, the subject selected for treatment is suffering from Stage 3 orStage 4 chronic kidney disease. In a further aspect, the subjectselected for treatment is suffering from end stage renal disease. In afurther aspect, the subject selected for treatment is suffering from oneor more of the following conditions: (a) diabetic nephropathy; (b) type2 diabetes; (c) Stage 3 chronic kidney disease, Stage 4 chronic kidneydisease, or end stage renal disease; (d) a urinary-albumin-to-creatinineratio greater than about 30 mg/g; (e) a urinary-albumin-to-creatinineratio greater than about 300 mg/g; and/or (f) an estimated glomerularfiltration rate from about 25 ml/min/1.73 m² to about 59 ml/min/1.73 m².In a further aspect, the subject is also administered a secondtherapeutic agent that inhibits one or more elements of therenin-angiotensin-aldosterone system. In a further aspect, the secondtherapeutic agent that inhibits one or more elements of therenin-angiotensin-aldosterone system is selected from the groupconsisting of diuretics, angiotensin converting enzyme inhibitors,angiotensin II receptor blockers, calcium channel blockers, renininhibitors, and aldosterone antagonists. In a further aspect, the secondtherapeutic agent that inhibits one or more elements of therenin-angiotensin-aldosterone system is selected from the groupconsisting of angiotensin converting enzyme inhibitors and angiotensinII receptor blockers.

In another embodiment, the present disclosure relates to methods ofreducing the urinary-albumin-to-creatinine ratio in a human subjectsuffering from or susceptible chronic kidney disease comprisingadministering once daily to the subject a stable solid pharmaceuticaldosage form comprising atrasentan, or a pharmaceutically acceptable saltthereof, as described in any of the embodiments of the disclosure.

In another embodiment, the present disclosure relates to methods ofreducing the rate of increase in serum creatinine concentration in ahuman subject suffering from or susceptible to chronic kidney diseasecomprising administering once daily to the subject a stable solidpharmaceutical dosage form comprising atrasentan, or a pharmaceuticallyacceptable salt thereof, as described in any of the embodiments of thedisclosure.

In another embodiment, the present disclosure relates to the use of astable solid pharmaceutical dosage form comprising atrasentan, or apharmaceutically acceptable salt thereof, for treating a condition asdescribed in the various embodiments of the disclosure.

IV. Combination Therapy and Fixed-Dose Combinations

The methods of the present disclosure also contemplate treatmentscomprising administering a stable solid pharmaceutical dosage formcomprising atrasentan, or a pharmaceutically acceptable salt thereof, asdescribed in any of the embodiments of the disclosure in combinationwith one or more additional therapeutic agents (such as an inhibitor ofone or more elements of the renin-angiotensin-aldosterone system aspreviously discussed above). Accordingly, the dosage forms of thepresent disclosure can be administered alone or in combination with oneor more additional therapeutic agents. When administered in combinationwith one or more additional therapeutic agents, separate dosage formscan be administered to the subject or a single dosage form comprisingboth atrasentan, or a pharmaceutically acceptable salt thereof, and theadditional therapeutic agent(s) can be administered to the subject. Ifadministered as a separate dosage form, the additional therapeutic agentmay be administered simultaneously with the atrasentan dosage form ofthe present disclosure or sequentially with the atrasentan dosage formof the present disclosure.

Representative additional therapeutic agents include, for example,diuretics, antihypertensive agents, therapeutic agents for diabetes ordiabetic complications, and therapeutic agents for hyperlipidemia.

In one embodiment, the dosage forms of the present disclosure may beco-administered with one or more diuretics such as hydroclorothiazide(such as MICROZIDE™ or ORETIC™), hydroflumethiazide (such as SALURON™),bemetanide (such as BUMEX™), torsemide (such as DEMADEX™), metolazone(such as ZAROXOLYN™), chlorothiazide (such as DIURIL™, ESIDRIX™ orHYDRODIURIL™), triamterene (such as DYRENIUM™), ethacrynic acid (such asEDECRIN™), chlorthalidone (such as HYGROTON™), furosemide (such asLASIX™), indapamide (such as LOZOL™), or amiloride (such as MIDAMOR™ orMODURETIC™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more angiotensin converting enzyme (ACE)inhibitors such as quinapril (such as ACCUPRIL™), perindopril (such asACEON™), captopril (such as CAPOTEN™), enalapril (such as VASOTEC™),ENALAPRILAT™, ramipril (such as ALTACE™), cilazapril, delapril,fosenopril (such as MONOPRIL™), zofenopril, indolapril, benazepril (suchas LOTENSIN™), lisinopril (such as PRINIVIL™ or ZESTRIL™), spirapril,trandolapril (such as MAVIK™), perindep, pentopril, moexipril (such asUNIVASC™), or pivopril.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more angiotensin II receptor blockers suchas candesartan (such as ATACAND™), eprosartan (such as TEVETEN™),irbesartan (such as AVEPRO™), losartan (such as COZAAR™), olmesartan,olmesartan medoxomil (such as BENICAR™), tasosartan, telmisartan (suchas MICARDIS™), valsartan (such as DIOVAN™), zolasartan, F1-6828K,RNH-6270, UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, or TA-606.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more calcium channel blockers such asnifedipine (such as ADALAT™, ADALAT CC™, or PROCARDIA™), verapamil (suchas GALAN™, COVERA-HS™, ISOPTIN SR™, or VERELAN™), diltiazem (such asCARDIZEM™, CARDIZEM CD™, CARDIZEM LA™, CARDIZEM SR™, DILACOR™, TIAMATE™,or TIAZAC™), isradipine (such as DYNACIRC™ or DYNACIRC CR™), amlodipine(such as NORVASC™), felodipine (such as PLENDIL™), nisoldipine (such asSULAR™), bepridil (such as VASCOR™), vatanidipine, clevidipine,lercanidipine, or dilitiazem.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more renin inhibitors such as aliskiren(such as TEKTURNA™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more aldosterone receptor antagonists suchas eplerenone (such as INSPRA™) or spironolactone (such as ALDACTONE™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more alpha blockers such as dozazosin (suchas CARDURA™) phenoxybenzamine (such as DIBENZYLINE™), terazosin (such asHYTRIN™), CDRl-93/478, or CR-2991.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more beta blockers such as timolol (such asBLOCARDEN™) carteolol (such as CARTROL™), carvedilol (such as COREG™),nadolol (such as CORGARD™), propranolol (such as INNOPRAN XL™),betaxolol (such as KERLONE™) penbutolol (such as LEVATOL™), metoprolol(such as LOPRESSOR™ or TOPROL-XL™), atenolol (such as TENORMIN™),pindolol (such as VISKEN™), or bisoprolol.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more alpha-beta blockers such as labetalol(such as NORMODYNE™ or TRANDATE™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more central antiadrenergics such asmethyldopa (such as ALDOMET™), clonidine (such as CATAPRES™ orCATAPRES-TTS™), guanfacine (such as TENEX™), or guanabenz (such asWYTENSIN™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more glycosides/inotropic agents such asdigoxin (such as LANOXIN™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more alpha glucosidase inhibitors, such asmiglitol (such as GLYSET™) or acarbose (such as PRECOSE™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more biguanides, such as roseiglitazone(such as AVANDAMET™) or metformin (such as GLUCOPHAGE™ or GLUCOPHAGEXR™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more insulins, such as HUMALOG™, HUMALOG50/50™, HUMALOG 75/25™, HUMULIN 50/50™, HUMALIN 75/25™, HUMALIN L™,HUMALIN N™, HUMALIN R™, HUMALIN R U-500™, HUMALIN U™, ILETIN II LENTE™,ILETIN II NPH™, ILETIN II REGULAR™, LANTUS™, NOVOLIN 70/30™, NOVILIN N™NOVILIN R™, NOVOLOG™, or VELOSULIN BR™, and EXUBERA™.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more meglitnides, such as repaglinide (suchas PRANDIN™) or nateglinide (such as STARLIX™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more sulfonylureas, such as glimepiride(such as AMARYL™), glyburide (such as DIABETA™, GLYNASE PRESTAB™ orMICRONASE™), or glipizide (such as GLUCOTROL™, or GLUCOTROL XL™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more thiazolidinediones, such aspioglitazone (such as ACTOS™) or rosiglitazone (such as AVANDIA™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with niacin or one or more nicotinic acid derivatives,such as NIACOR™ NIASPAN™, NICOLAR™, or SLO-NIACIN™.

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more fibric acid derivatives, such asclofibrate (such as ATROMID-S™), gemfibrozil (such as LOPID™), orfenofibrate (such as TRICOR™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more bile acid sequestants, such ascolestipol (such as COLESTID™), cholestyramine (such as LOCHOLEST™,PREVALITE™, QUESTRAN™, or QUESTRAN LIGHT™), or colesevelam (such asWELCHOL™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more cholesterol absorption inhibitors, suchas ezetimibe (such as ZETIA™).

In another embodiment, the dosage forms of the present disclosure may beco-administered with one or more 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors (statins) such as fluvastatin (such asLESCOL™), atorvastatin (such as LIPITOR™), lovastatin (such as ALTOCOR™or MEVACOR™), pravastatin (such as PRAVACHOL™), rosuvastatin (such asCRESTOR™), or simvastatin (such as ZOCOR™).

In another embodiment, the present disclosure relates to the use of afirst dosage form in combination with a second dosage form for treatinga condition as described in the various embodiments of the disclosure,wherein the first dosage form is a stable solid pharmaceutical dosageform comprising atrasentan, or a pharmaceutically acceptable saltthereof, as described in any of the embodiments of the disclosure, andthe second dosage form comprises a second therapeutic agent.

In another embodiment, the present disclosure relates to the use of astable solid pharmaceutical dosage form comprising atrasentan, or apharmaceutically acceptable salt thereof, for treating a condition asdescribed in the various embodiments of the disclosure, wherein thedosage form further comprises a second therapeutic agent.

In another embodiment, the present disclosure relates to a stable solidpharmaceutical dosage form comprising atrasentan, or a pharmaceuticallyacceptable salt thereof, and further comprising a second therapeuticagent. In one aspect, the second therapeutic agent inhibits one or moreelements of the renin-angiotensin-aldosterone system. In a furtheraspect, the second therapeutic agent is selected from the groupconsisting of diuretics, angiotensin converting enzyme inhibitors,angiotensin II receptor blockers, calcium channel blockers, renininhibitors, and aldosterone antagonists. In a further aspect, the secondtherapeutic agent is selected from the group consisting of angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers. In afurther aspect, the second therapeutic agent is an angiotensinconverting enzyme inhibitor. In a further aspect, the second therapeuticagent is an angiotensin II receptor blocker.

V. Kits

The present disclosure also relates to kits comprising one or morestable solid pharmaceutical dosage forms comprising atrasentan, or apharmaceutically acceptable salt thereof, as described in any of theembodiments of the disclosure. The kit optionally can comprise one ormore additional therapeutic agents and/or instructions, for example,instructions for using the kit.

In one embodiment, the kit comprises a semi-permeable containercontaining one or more stable solid pharmaceutical dosage formscomprising atrasentan, or a pharmaceutically acceptable salt thereof, asdescribed in any of the embodiments of the disclosure. In one aspect,the semi-permeable container is a blister pack.

In another embodiment, the kit comprises a substantially impermeablecontainer containing one or more stable solid pharmaceutical dosageforms comprising atrasentan, or a pharmaceutically acceptable saltthereof, as described in any of the embodiments of the disclosure.

In another embodiment, the kit comprises a first dosage form and asecond dosage form, wherein the first dosage form is a stable solidpharmaceutical dosage form comprising atrasentan, or a pharmaceuticallyacceptable salt thereof, as described in any of the embodiments of thedisclosure, and the second dosage form comprises a second therapeuticagent. In a further aspect, the second therapeutic agent is selectedfrom the group consisting of diuretics, angiotensin converting enzymeinhibitors, angiotensin II receptor blockers, calcium channel blockers,renin inhibitors, and aldosterone antagonists. In a further aspect, thesecond therapeutic agent is selected from the group consisting ofangiotensin converting enzyme inhibitors and angiotensin II receptorblockers. In a further aspect, the second therapeutic agent is anangiotensin converting enzyme inhibitor. In a further aspect, the secondtherapeutic agent is an angiotensin II receptor blocker. In a furtheraspect, the kit comprises a semi-permeable container containing thefirst dosage form and the second dosage form. In a further aspect, thekit comprises a blister pack containing the first dosage form and thesecond dosage form. In a further aspect, the kit comprises animpermeable container containing the first dosage form and the seconddosage form.

VI. Methods of Preparation

The present disclosure also relates to methods for preparing a stablesolid pharmaceutical dosage form comprising about 0.25 mg to about 1.25mg of atrasentan, or pharmaceutically acceptable salt thereof, asdescribed in any of the embodiments of the disclosure. In general, thesedosage forms can be prepared using conventional techniques known in theart such as, but not limited to, direct blending, dry granulation(roller compaction), wet granulation (high shear granulation), millingor sieving, drying (if wet granulation is used), compression, and,optionally, coating. It is believed, however, that dosage form stabilityimproves when the low dose of atrasentan, or pharmaceutically acceptablesalt thereof, is first combined with at least a portion of apharmaceutically acceptable polymeric binder to form a first mixture andthe first mixture is then blended with the remaining components duringthe preparation of the dosage form. It is further believed that it isadditionally advantageous to include a pharmaceutically acceptableanti-oxidant as one of the components during the preparation of thedosage form.

A. Pre-Treatment of Atrasentan with HPMC

In one embodiment, the present disclosure relates to methods for thepreparation of a stable solid pharmaceutical dosage form comprisingabout 0.25 mg to about 1.25 mg of atrasentan, or pharmaceuticallyacceptable salt thereof, as described in any of the embodiments of thedisclosure; wherein the method comprises:

(a) combining the atrasentan, or a pharmaceutically acceptable saltthereof, with at least a portion of a pharmaceutically acceptablepolymeric binder to form a first mixture;

(b) blending the first mixture with a pharmaceutically acceptablediluent to form a second mixture; and

(c) encapsulating or tableting the second mixture to yield the dosageform.

In one aspect, the first mixture is a liquid mixture. In another aspect,the first mixture is a liquid mixture, the blending step comprises wetgranulation, and the first mixture is used as a granulating agent. Inanother aspect, the first mixture is a dry mixture. In another aspect,the first mixture is a dry mixture and the first mixture is compressedbefore it is blended with the diluent.

In another embodiment, the present disclosure relates to methods for thepreparation of a stable solid pharmaceutical dosage form as described inany of the embodiments of the disclosure; wherein the dosage formcomprises about 0.25 mg to about 1.25 mg of atrasentan, orpharmaceutically acceptable salt thereof; a pharmaceutically acceptableanti-oxidant; a pharmaceutically acceptable diluent; and apharmaceutically acceptable polymeric binder selected from the groupconsisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose,and hydroxypropylcellulose; and wherein the method comprises:

(a) combining the atrasentan, or a pharmaceutically acceptable saltthereof, with at least a portion of the polymeric binder to form a firstmixture;

(b) blending the first mixture with the diluent to form a secondmixture; and

(c) encapsulating or tableting the second mixture to yield the dosageform.

In one aspect, the polymeric binder is hydroxypropyl methylcellulose. Inanother aspect, the polymeric binder is hydroxypropylethylcellulose. Inanother aspect, the polymeric binder is hydroxypropylcellulose. Inanother aspect, the weight percent of the polymeric binder in the dosageform is from about 1.0 weight percent to about 10.0 weight percent. Inanother aspect, the first mixture is a liquid mixture. In anotheraspect, the first mixture is a liquid mixture, the blending stepcomprises wet granulation, and the first mixture is used as agranulating agent. In another aspect, the first mixture is a drymixture. In another aspect, the first mixture is a dry mixture and thefirst mixture is compressed before it is blended with the diluent.

Where the first mixture is a liquid mixture, the liquid mixturecomprises a pharmaceutically acceptable liquid such as water. In oneaspect, the first mixture is an aqueous mixture. In another aspect, thefirst mixture is an aqueous suspension of atrasentan, or apharmaceutically acceptable salt thereof. In another aspect, the firstmixture is an aqueous solution of atrasentan, or a pharmaceuticallyacceptable salt thereof. In another aspect, the first mixture is anaqueous mixture, the blending step comprises wet granulation, and thefirst mixture is used as a granulating agent. In another aspect of thevarious embodiments employing wet granulation, a first portion of thepolymeric binder is combined with the atrasentan, or a pharmaceuticallyacceptable salt thereof, to prepare the first mixture, and a secondportion of the polymeric binder is added to the granulation bowl used toprepare the second mixture.

In one embodiment, the liquid mixture has a viscosity that is sufficientto maintain the atrasentan, or pharmaceutically acceptable salt thereof,in suspension.

In another embodiment, the atrasentan, or pharmaceutically acceptablesalt thereof, is dissolved in the liquid mixture.

In another embodiment, the weight percent of the polymeric binder in theliquid mixture is from about 0.5 weight percent to about 15.0 weightpercent. In another aspect, the weight percent of the polymeric binderis from about 0.5 weight percent to about 12.0 weight percent. Inanother aspect, the weight percent of the polymeric binder is from about0.5 weight percent to about 10.0 weight percent.

In another embodiment, the weight percent of the atrasentan, orpharmaceutically acceptable salt thereof, in the liquid mixture is fromabout 2.0 weight percent to about 12.0 weight percent. In anotheraspect, the weight percent of atrasentan, or pharmaceutically acceptablesalt thereof, is from about 3.0 weight percent to about 10.0 weightpercent. In another aspect, the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, is from about 4.0 weightpercent to about 8.0 weight percent.

In another embodiment, the weight to weight ratio of the polymericbinder to atrasentan, or a pharmaceutically acceptable salt thereof, inthe liquid mixture is from about 5:1 to about 1:5. In one aspect, theweight to weight ratio of the polymeric binder to atrasentan, or apharmaceutically acceptable salt thereof, is from about 3.5:1 to about1:3.5. In another aspect, the weight to weight ratio of the polymericbinder to atrasentan, or a pharmaceutically acceptable salt thereof, inthe first mixture is from about 1:2 to about 2:1.

In another embodiment, at least two of the following conditions aresatisfied: (a) the weight percent of the polymeric binder in the liquidmixture is from about 0.5 weight percent to about 15.0 weight percent;(b) the weight percent of atrasentan, or pharmaceutically acceptablesalt thereof, in the first mixture is from about 2.0 weight percent toabout 12.0 weight percent; and/or (c) the weight to weight ratio of thepolymeric binder to atrasentan, or a pharmaceutically acceptable saltthereof, in the first mixture is from about 5:1 to about 1:5 on anatrasentan free base equivalent weight basis. In one aspect, at leasttwo of the following conditions are satisfied: (a) the weight percent ofthe polymeric binder in the liquid mixture is from about 0.5 weightpercent to about 12.0 weight percent; (b) the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in the firstmixture is from about 3.0 weight percent to about 10.0 weight percent;and/or (c) the weight to weight ratio of the polymeric binder toatrasentan, or a pharmaceutically acceptable salt thereof, in the firstmixture is from about 3.5:1 to about 1:3.5 on an atrasentan free baseequivalent weight basis. In another aspect, at least two of thefollowing conditions are satisfied: (a) the weight percent of thepolymeric binder in the liquid mixture is from about 0.5 weight percentto about 10.0 weight percent; (b) the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, in the first mixture is fromabout 4.0 weight percent to about 8.0 weight percent; and/or (c) theweight to weight ratio of the polymeric binder to atrasentan, or apharmaceutically acceptable salt thereof, in the first mixture is fromabout 1:2 to about 2:1 on an atrasentan free base equivalent weightbasis.

In each of the above-discussed methods, the second mixture additionallymay comprise an anti-oxidant, a disintegrant, a glidant, and/or alubricant. In one aspect, the second mixture comprises an anti-oxidant.In another aspect, the second mixture comprises a disintegrant. Inanother aspect, the second mixture comprises a glidant. In anotheraspect, the second mixture comprises a lubricant. In another aspect, thesecond mixture comprises an anti-oxidant, a disintegrant, a glidant, anda lubricant. In another aspect, the anti-oxidant is L-cysteine, or apharmaceutically acceptable salt or ester thereof. In another aspect,the second mixture comprises L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof, a disintegrant, a glidant, and alubricant.

B. Atrasentan-Coated Tablet

The stable solid pharmaceutical dosage form comprising about 0.25 mg toabout 1.25 mg of atrasentan, or pharmaceutically acceptable saltthereof, as described in any of the embodiments of the disclosure alsocan be prepared as an atrasentan-coated tablet (i.e., a tablet coatedwith atrasentan). In one embodiment, the present disclosure relates tomethods for the preparation of a stable solid pharmaceutical dosage formcomprising about 0.25 mg to about 1.25 mg of atrasentan, orpharmaceutically acceptable salt thereof, as described in any of theembodiments of the disclosure; wherein the method comprises:

(a) combining the atrasentan, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable polymer selected from thegroup consisting of hydroxymethylpropylcellulose,hydroxyethylpropylcellulose, and hydroxypropylcellulose to form acoating mixture; and

(b) applying the coating mixture to the surface of a tablet corecomprising a pharmaceutically acceptable diluent to yield the dosageform.

In one aspect, one or both of the following conditions are satisfied:(a) the weight percent of atrasentan, or pharmaceutically acceptablesalt thereof, in the dosage form is from about 0.05 weight percent toabout 2.0 weight percent on an atrasentan free base equivalent weightbasis; and/or (b) the weight percent of the polymer in the dosage formis from about 0.5 weight percent to about 15.0 weight percent. Inanother aspect, the polymer is hydroxypropyl methylcellulose. In anotheraspect, the polymer is hydroxypropylethylcellulose. In another aspect,the polymer is hydroxypropylcellulose.

In various additional embodiments, the tablet additionally may comprisean anti-oxidant, a disintegrant, a glidant, and/or a lubricant. In oneaspect, the tablet comprises an anti-oxidant. In another aspect, thetablet comprises a disintegrant. In another aspect, the tablet comprisesa glidant. In another aspect, the tablet comprises a lubricant. Inanother aspect, the tablet comprises an anti-oxidant, a disintegrant, aglidant, and a lubricant. In another aspect, the anti-oxidant isL-cysteine, or a pharmaceutically acceptable salt or ester thereof. Inanother aspect, the tablet comprises L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof, a disintegrant, a glidant, and alubricant.

In an alternative embodiment, step (b) of the above-described methodinstead involves applying the coating mixture to the surface ofparticles (e.g., beads, granules, pellets, or the like) comprising apharmaceutically acceptable diluent, and then compressing orencapsulating the coated particles to yield the dosage form.

VII. Product-by-Process

The present disclosure also relates to stable solid pharmaceuticaldosage forms that are prepared in accordance with one of theabove-described methods and comprise about 0.25 mg to about 1.25 mg ofatrasentan, or pharmaceutically acceptable salt thereof, as described inany of the embodiments of the disclosure. In one aspect, the dosage formis prepared in accordance with the above-described method in which theatrasentan, or pharmaceutically acceptable salt thereof, is pre-treatedwith the HPMC. In another aspect, the dosage form is prepared inaccordance with the above-described method in which an atrasentan-coatedtablet is prepared.

A. Product-by-Process: Pre-Treatment of Atrasentan with HPMC

In one embodiment, the present disclosure relates to a stable solidpharmaceutical dosage form comprising about 0.25 mg to about 1.25 mg ofatrasentan, or a pharmaceutically acceptable salt thereof, as describedin any of the embodiments of the disclosure wherein:

the dosage form comprises a pharmaceutically acceptable polymeric binderselected from the group consisting of hydroxymethylpropylcellulose,hydroxyethylpropylcellulose, and hydroxypropylcellulose;

the dosage form is prepared by:

(a) combining at least a portion of the atrasentan, or apharmaceutically acceptable salt thereof, with at least a portion of thepolymeric binder to form a first mixture;

(b) blending the first mixture with the diluent to form a secondmixture; and

(c) encapsulating or tableting the second mixture to yield the dosageform; and

degradation of atrasentan in the dosage form is less than degradation ofatrasentan in an otherwise identical dosage form lacking the polymericbinder when the dosage forms are stored for a storage period of sixmonths at about 40° C. and about 75% relative humidity.

In one aspect, the dosage form further comprises a pharmaceuticallyacceptable anti-oxidant, and degradation of atrasentan in the dosageform is less than degradation of atrasentan in an otherwise identicaldosage form lacking the anti-oxidant and the polymeric binder when thedosage forms are stored for a storage period of six months at about 40°C. and about 75% relative humidity.

In another embodiment, the polymeric binder is hydroxypropylmethylcellulose. In one aspect, the polymeric binder ishydroxypropylethylcellulose. In another aspect, the polymeric binder ishydroxypropylcellulose. In another aspect, the weight percent of thepolymeric binder in the dosage form is from about 1.0 weight percent toabout 10.0 weight percent. In another aspect, the first mixture is aliquid mixture. In another aspect, the first mixture is a liquidmixture, the blending step comprises wet granulation, and the firstmixture is used as a granulating agent. In another aspect, the firstmixture is a dry mixture. In another aspect, the first mixture is a drymixture and the first mixture is compressed before it is blended withthe diluent.

Where the first mixture is a liquid mixture, the liquid mixturecomprises a pharmaceutically acceptable liquid such as water. In oneaspect, the first mixture is an aqueous mixture. In another aspect, thefirst mixture is an aqueous suspension of atrasentan, or apharmaceutically acceptable salt thereof. In another aspect, the firstmixture is an aqueous solution of atrasentan, or a pharmaceuticallyacceptable salt thereof. In another aspect, the first mixture is anaqueous mixture, the blending step comprises wet granulation, and thefirst mixture is used as a granulating agent. In another aspect ofembodiments employing wet granulation, a first portion of the polymericbinder is combined with the atrasentan, or a pharmaceutically acceptablesalt thereof, to prepare the first mixture and a second portion of thepolymeric binder is added to the granulation bowl used to prepare thesecond mixture.

In one embodiment, the liquid mixture has a viscosity that is sufficientto maintain the atrasentan, or pharmaceutically acceptable salt thereof,in suspension.

In another embodiment, the atrasentan, or pharmaceutically acceptablesalt thereof, is dissolved in the liquid mixture.

In another embodiment, the weight percent of the polymeric binder in theliquid mixture is from about 0.5 weight percent to about 15.0 weightpercent. In another aspect, the weight percent of the polymeric binderis from about 0.5 weight percent to about 12.0 weight percent. Inanother aspect, the weight percent of the polymeric binder is from about0.5 weight percent to about 10.0 weight percent.

In another embodiment, the weight percent of the atrasentan, orpharmaceutically acceptable salt thereof, in the liquid mixture is fromabout 2.0 weight percent to about 12.0 weight percent. In anotheraspect, the weight percent of atrasentan, or pharmaceutically acceptablesalt thereof, is from about 3.0 weight percent to about 10.0 weightpercent. In another aspect, the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, is from about 4.0 weightpercent to about 8.0 weight percent.

In another embodiment, the weight to weight ratio of the polymericbinder to atrasentan, or a pharmaceutically acceptable salt thereof, inthe liquid mixture is from about 5:1 to about 1:5. In one aspect, theweight to weight ratio of the polymeric binder to atrasentan, or apharmaceutically acceptable salt thereof, is from about 3.5:1 to about1:3.5. In another aspect, the weight to weight ratio of the polymericbinder to atrasentan, or a pharmaceutically acceptable salt thereof, inthe first mixture is from about 1:2 to about 2:1.

In another embodiment, at least two of the following conditions aresatisfied: (a) the weight percent of the polymeric binder in the liquidmixture is from about 0.5 weight percent to about 15.0 weight percent;(b) the weight percent of atrasentan, or pharmaceutically acceptablesalt thereof, in the first mixture is from about 2.0 weight percent toabout 12.0 weight percent; and/or (c) the weight to weight ratio of thepolymeric binder to atrasentan, or a pharmaceutically acceptable saltthereof, in the first mixture is from about 5:1 to about 1:5 on anatrasentan free base equivalent weight basis. In one aspect, at leasttwo of the following conditions are satisfied: (a) the weight percent ofthe polymeric binder in the liquid mixture is from about 0.5 weightpercent to about 12.0 weight percent; (b) the weight percent ofatrasentan, or pharmaceutically acceptable salt thereof, in the firstmixture is from about 3.0 weight percent to about 10.0 weight percent;and/or (c) the weight to weight ratio of the polymeric binder toatrasentan, or a pharmaceutically acceptable salt thereof, in the firstmixture is from about 3.5:1 to about 1:3.5 on an atrasentan free baseequivalent weight basis. In another aspect, at least two of thefollowing conditions are satisfied: (a) the weight percent of thepolymeric binder in the liquid mixture is from about 0.5 weight percentto about 10.0 weight percent; (b) the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, in the first mixture is fromabout 4.0 weight percent to about 8.0 weight percent; and/or (c) theweight to weight ratio of the polymeric binder to atrasentan, or apharmaceutically acceptable salt thereof, in the first mixture is fromabout 1:2 to about 2:1 on an atrasentan free base equivalent weightbasis.

In each of the above-discussed methods, the second mixture additionallymay comprise an anti-oxidant, a disintegrant, a glidant, and/or alubricant. In one aspect, the second mixture comprises an anti-oxidant.In another aspect, the second mixture comprises a disintegrant. Inanother aspect, the second mixture comprises a glidant. In anotheraspect, the second mixture comprises a lubricant. In another aspect, thesecond mixture comprises an anti-oxidant, a disintegrant, a glidant, anda lubricant. In another aspect, the anti-oxidant is L-cysteine, or apharmaceutically acceptable salt or ester thereof. In another aspect,the second mixture comprises L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof, a disintegrant, a glidant, and alubricant.

B. Product-by-Process: Atrasentan-Coated Tablet

In one embodiment, the present disclosure relates to a stable solidpharmaceutical dosage form comprising about 0.25 mg to about 1.25 mg ofatrasentan, or a pharmaceutically acceptable salt thereof, as describedin any of the embodiments of the disclosure wherein: the dosage form isprepared by:

(a) combining atrasentan, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable polymer selected from the groupconsisting of hydroxymethylpropylcellulose, hydroxyethylpropylcellulose,and hydroxypropylcellulose to form a coating mixture; and

(b) applying the coating mixture to the surface of a tablet corecomprising a pharmaceutically acceptable diluent to yield the dosageform; and

degradation of atrasentan in the dosage form is less than degradation ofatrasentan in an otherwise identical dosage form lacking the polymerwhen the dosage forms are stored for a storage period of six months atabout 40° C. and about 75% relative humidity.

In another embodiment, one or both of the following conditions aresatisfied: (a) the weight percent of atrasentan, or pharmaceuticallyacceptable salt thereof, in the dosage form is from about 0.05 weightpercent to about 2.0 weight percent on an atrasentan free baseequivalent weight basis; and/or (b) the weight percent of the polymer inthe dosage form is from about 0.5 weight percent to about 15.0 weightpercent. In another aspect, the polymer is hydroxypropylmethylcellulose. In another aspect, the polymer ishydroxypropylethylcellulose. In another aspect, the polymer ishydroxypropylcellulose.

In various additional embodiments, the tablet additionally may comprisean anti-oxidant, a disintegrant, a glidant, and/or a lubricant. In oneaspect, the tablet comprises an anti-oxidant. In one aspect, theanti-oxidant is L-cysteine, or a pharmaceutically acceptable salt orester thereof. In one aspect, the tablet comprises a disintegrant. Inanother aspect, the tablet comprises a glidant. In another aspect, thetablet comprises a lubricant. In another aspect, the tablet comprises ananti-oxidant, a disintegrant, a glidant, and a lubricant.

In an alternative embodiment, the dosage form is prepared in accordancewith the above-described method except that step (b) instead involvesapplying the coating mixture to the surface of particles (e.g., beads,granules, pellets, or the like) comprising a pharmaceutically acceptablediluent, and then compressing or encapsulating the coated particles toyield the dosage form.

VIII. Examples Example 1 Analytical Methods

A. Atrasentan and Impurities Content

High-performance liquid chromatography (“HPLC”) was used to determinethe amount of atrasentan and the amount of impurities (i.e., atrasentandegradation products) contained in the tablets analyzed in the stabilitytesting reported in the following Examples. Although minor changes weremade to the HPLC conditions used to determine the amount of atrasentanover the course of stability testing, the changes did not materiallyaffect the measured values. Descriptions of the initial and the modifiedHPLC conditions employed to generate data reported in the followingExamples are provided in Tables 1-A through 1-C. The HPLC conditionsused to determine the amount of impurities reported in the followingExamples were not modified over the course of stability testing and adescription of those HPLC conditions is provided in Table 1-D.

(i) Atrasentan Sample Preparation Procedure (Assay)

(a) 0.35 mg Tablets

Ten tablets are transferred into a 200.0 mL volumetric flask.Approximately 120 mL of the Diluent is added to the flask. Using amechanical shaker, the flask is shaken for approximately 2 hours. Theflask contents are diluted to volume with the Diluent and mixed well.Approximately 20 mL of the resulting solution is filtered through a0.45-micron nylon filter, sending the initial portion of about 5 mL towaste and collecting about 10 mL for further use.

(b) 0.50 mg Tablets

Ten tablets are transferred into a 250.0 mL volumetric flask.Approximately 150 mL of the Diluent is added to the flask. Using amechanical shaker, the flask is shaken for approximately 2 hours. Theflask contents are diluted to volume with the Diluent and mixed well.Approximately 20 mL of the resulting solution is filtered through a0.45-micron nylon filter, sending the initial portion of about 5 mL towaste and collecting about 10 mL for further use.

(c) 0.75 mg Tablets

Seven tablets are transferred into a 250.0 mL volumetric flask.Approximately 150 mL of the Diluent is added to the flask. Using amechanical shaker, the flask is shaken for approximately 2 hours. Theflask contents are diluted to volume with the Diluent and mixed well.Approximately 20 mL of the resulting solution is filtered through a0.45-micron nylon filter, sending the initial portion of about 5 mL towaste and collecting about 10 mL for further use.

(ii) Atrasentan Sample Preparation Procedure (Content Uniformity)

(a) 0.35 mg Tablets

One tablet is transferred into a 20.0 mL volumetric flask. Approximately12 mL of the Diluent is added to the flask. Using a mechanical shaker,the flask is shaken for approximately 2 hours. The flask contents arediluted to volume with the Diluent and mixed well. Approximately 20 mLof the resulting solution is filtered through a 0.45-micron nylonfilter, sending the initial portion of about 5 mL to waste andcollecting about 10 mL for further use.

(b) 0.50 mg Tablets

One tablet is transferred into a 25.0 mL volumetric flask. Approximately15 mL of the Diluent is added to the flask. Using a mechanical shaker,the flask is shaken for approximately 2 hours. The flask contents arediluted to volume with the Diluent and mixed well. Approximately 20 mLof the resulting solution is filtered through a 0.45-micron nylonfilter, sending the initial portion of about 5 mL to waste andcollecting about 10 mL for further use.

(c) 0.75 mg Tablets

One tablet is transferred into a 50.0 mL volumetric flask. Approximately30 mL of the Diluent is added to the flask. Using a mechanical shaker,the flask is shaken for approximately 2 hours. The flask contents arediluted to volume with the Diluent and mixed well. Approximately 20 mLof the resulting solution is filtered through a 0.45-micron nylonfilter, sending the initial portion of about 5 mL to waste andcollecting about 10 mL for further use.

(iii) Impurities Sample Preparation Procedure

(a) 0.35 mg Tablets

Fourteen tablets are transferred into a 50-mL volumetric flask.Approximately 25 mL of the High Organic Diluent is added to the flask.Using a mechanical shaker, the flask is shaken for approximately 120minutes. The flask contents are diluted to volume using the High OrganicDiluent and mixed well. A portion of the resulting solution is filteredthrough a 0.45-micron Nylon membrane, sending the initial portion ofabout 5 mL to waste. A 2.0 mL portion of the filtered solution isdiluted to a volume of 10.0 mL using a 10 mM Formate buffer and mixedwell.

(b) 0.50 mg Tablets

Ten tablets are transferred into a 50-mL volumetric flask. Approximately25 mL of the High Organic Diluent is added to the flask. Using amechanical shaker, the flask is shaken for approximately 120 minutes.The flask contents are diluted to volume using the High Organic Diluentand mixed well. A portion of the resulting solution is filtered througha 0.45-micron Nylon membrane, sending the initial portion of about 5 mLto waste. A 2.0 mL portion of the filtered solution is diluted to avolume of 10.0 mL using a 10 mM Formate buffer and mixed well.

(c) 0.75 mg Tablets

Six tablets are transferred into a 50-mL volumetric flask. Approximately25 mL of the High Organic Diluent is added to the flask. Using amechanical shaker, the flask is shaken for approximately 120 minutes.The flask contents are diluted to volume using the High Organic Diluentand mixed well. A portion of the resulting solution is filtered througha 0.45-micron Nylon membrane, sending the initial portion of about 5 mLto waste. A 2.0 mL portion of the filtered solution is diluted to avolume of 10.0 mL using a 10 mM Formate buffer and mixed well.

(iv) HPLC Conditions

TABLE 1-A Atrasentan Assay HPLC Conditions (Version 1) PARAMETERCONDITIONS Technique HPLC Column C₁₈, 2.6 micron, 150 × 3.0 mm, 35° C.Mobile Phase A 95/5 10 mM Ammonium Formate Buffer pH 3.2/AcetonitrileMobile Phase B 85/15 Acetonitrile/50 mM Ammonium Formate Buffer pH 3.2Gradient Time (min) % A % B Elution 0 60 40 25 60 40 25.1 10 90 31.0 1090 31.1 60 40 40 60 40 Flow Rate Approximately 0.5 mL/minute Injectionvolume 10 μL Detection UV at 234 nm Diluent 10 mM Ammonium FormateBuffer, pH 3.2:Acetonitrile (25:75) Solution Concentrations StandardApproximately 19 μg atrasentan*/mL in Diluent Sample: Approximately 20μg atrasentan*/mL Assay and Content in Diluent (Blend) UniformityApproximately 20 μg atrasentan*/mL in Diluent (0.50 mg Tablet)Approximately 30 μg atrasentan*/mL in Diluent (0.75 mg Tablet) *Freebase equivalent weight

TABLE 1-B Atrasentan Assay HPLC Conditions (Version 2) PARAMETERCONDITIONS Technique HPLC Column C₁₈, 2.6 micron, 150 × 3.0 mm, 35° C.Mobile Phase A 63/37 8.7 mM Ammonium Formate Buffer pH 3.2/AcetonitrileMobile Phase B 77/23 Acetonitrile/7.7 mM Ammonium Formate Buffer pH 3.2Gradient Time (min) % A % B Elution 0 100 0 25 100 0 25.1 0 100 31.0 0100 31.1 100 0 40 100 0 Flow Rate Approximately 0.5 mL/minute Injectionvolume 10 μL Detection UV at 234 nm Diluent 10 mM Ammonium FormateBuffer, pH 3.2:Acetonitrile (25:75) Solution Concentrations StandardApproximately 19 μg atrasentan*/mL in Diluent Sample: AssayApproximately 20 μg atrasentan*/mL in Diluent (Blend) Approximately 18μg atrasentan*/mL in Diluent (0.35 mg Tablet) Approximately 20 μgatrasentan*/mL in Diluent (0.50 mg Tablet) Approximately 21 μgatrasentan*/mL in Diluent (0.75 mg Tablet) Sample: Approximately 18 μgatrasentan*/mL in Content Diluent (0.35 mg Tablet) UniformityApproximately 20 μg atrasentan*/mL in Diluent (0.50 mg Tablet)Approximately 15 μg atrasentan*/mL in Diluent (0.75 mg Tablet) *Freebase equivalent weight

TABLE 1-C Atrasentan Assay HPLC Conditions (Version 3) PARAMETERCONDITIONS Technique HPLC Column C₁₈, 2.6 micron, 150 × 3.0 mm, 35° C.Mobile Phase A 60/40 10 mM Ammonium Formate Buffer pH 3.2/AcetonitrileElution Isocratic Flow Rate Approximately 0.5 mL/minute Injection volume10 μL Detection UV at 234 nm Diluent 10 mM Ammonium Formate Buffer, pH3.2:Acetonitrile (25:75) Solution Concentrations Standard Approximately19 μg atrasentan*/mL in Diluent Sample: Assay Approximately 20 μgatrasentan*/mL in Diluent (Blend) Approximately 18 μg atrasentan*/mL inDiluent (0.35 mg Tablet) Approximately 20 atrasentan*/mL in Diluent(0.50 mg Tablet) Approximately 21 μg atrasentan*/mL in Diluent (0.75 mgTablet) Sample: Approximately 18 μg atrasentan*/mL in Diluent Content(0.35 mg Tablet) Uniformity Approximately 20 μg atrasentan*/mL inDiluent (0.50 mg Tablet) Approximately 15 μg atrasentan*/mL in Diluent(0.75 mg Tablet) *Free base equivalent weight

TABLE 1-D Impurities Assay HPLC Conditions PARAMETER CONDITIONSTechnique HPLC Column C₁₈, 2.6 micron, 150 × 3.0 mm, 35° C. Mobile PhaseA 10 mM Ammonium Formate Buffer, pH 3.2:Acetonitrile (95:5) Mobile PhaseB 50 mM Ammonium Formate Buffer, pH 3.2:Acetonitrile (15:85) Time (min)% A % B Gradient Profile 0 95 5 22 60 40 29 60 40 55 5 95 60 5 95 60.195 5 70 95 5 Flow Rate Approximately 0.5 mL/minute Injection volume 75μL Detection UV at 234 nm Practical Detection Limit 0.05% Diluent HighOrganic 10 mM Ammonium Formate Buffer, pH 3.2:Acetonitrile (25:75) LowOrganic 10 mM Ammonium Formate Buffer, pH 3.2:Acetonitrile (85:15)Solution Concentrations Practical Detection Limit Approximately 0.009 μgatrasentan*/mL in Low Organic Diluent Standard Approximately 0.09 μgatrasentan*/mL in Low Organic Diluent Sample: Assay Approximately 20 μgatrasentan*/mL in solution equivalent to Low Organic Diluent (0.50 mgtablets) Approximately 18 μg atrasentan*/mL mL in solution equivalent toLow Organic Diluent (0.75 mg tablets) *Free base equivalent weight

B. Moisture Content

The moisture content data reported in the following Examples weredetermined using Karl Fisher titration. Further information on thetitration is provided in Table 1-E below.

TABLE 1-E Tablet Moisture Content Method PARAMETER CONDITIONS TechniqueVolumetric Karl Fischer Reagent Hydranal-Composite 5, Fluka DiluentMethanol Sample Size 1 gram composite of 12 tablets

C. Dissolution Profile

The tablet dissolution profile data reported in the following Exampleswere generated using a USP Dissolution Apparatus 2 and HPLC as theanalytical method. Further information on the dissolution testing andHPLC analytical method is provided in Table 1-F below.

TABLE 1-F Tablet Dissolution Profile Method PARAMETER CONDITIONSTechnique HPLC Column C₁₈, 5 micron, 150 × 4.6 mm, 25° C. Mobile Phase50/50 50 mM Phosphate Buffer pH 2.6/Acetonitrile Elution Isocratic FlowRate Approximately 1.0 mL/minute Injection volume 100 μL Detection UV at234 nm Apparatus USP Dissolution Apparatus 2 and Syringe-driven fractioncollector Medium 900 mL of 0.01N HCl Temperature 37° C. RPM 50 RPMSampling Times 15, 30, 45, 60 Minutes Diluent Samples Diluted 1:1 withmobile phase Solution Concentrations Standard Approximately 0.21 μgatrasentan*/mL in Diluent *Free base equivalent weight

Example 2 Phase IIb Tablet Stability

Atrasentan dosage forms having the compositions shown in Table 2-A (0.35mg tablet), Table 2-B (0.50 mg tablet), and Table 2-C (0.75 mg tablet)below were prepared and used in Phase IIb clinical trials to evaluatethe safety and efficacy of atrasentan in treating subjects with diabeticnephropathy. The tablets were prepared using a wet granulation processand were compressed into round tablets having a core weight of 120 mgand a diameter of 6.5 mm.

TABLE 2-A Phase IIb Tablet (0.35 mg) TABLET CORE COMPOSITION INGREDIENTWEIGHT/WEIGHT % mg/TABLET Atrasentan 0.31 0.37^(a) MonohydrochlorideLactose Monohydrate 91.19 109.4 (Regular) Hypromellose E5 3.00 3.6(Premium LV) Crospovidone 3.50 4.2 (POLYPLASDONE ™ XL) Silicon Dioxide(SYLOID ®) 0.50 0.6 Glyceryl Behenate 1.50 1.8 (COMPRITOL ®) Purifiedwater^(b) n/a n/a Total 100% 120 mg FILM COATED TABLET COMPOSITIONINGREDIENT WEIGHT/WEIGHT %^(c) mg/TABLET^(d) PEG1450 3 0.1 HypromelloseE5 97 3.5 (Premium LV) Purified Water N/a n/a ^(a)Atrasentanmonohydrochloride salt factor = 1.07 (i.e., 0.35 mg free base × 1.07 =0.37 mg salt). ^(b)Granulation suspension medium. Less than 2% presentin final product. ^(c)Based on an aqueous solution of 10% solids.^(d)Based on a 120 mg tablet weight with a coating weight gain of 3%.

TABLE 2-B Phase IIb Tablet (0.50 mg) TABLET CORE COMPOSITION INGREDIENTWEIGHT/WEIGHT % mg/TABLET Atrasentan 0.4460 0.5350^(a) MonohydrochlorideLactose Monohydrate 91.05 109.3 (Regular) Hypromellose E5 3.000 3.600(Premium LV) Crospovidone 3.500 4.200 (POLYPLASDONE ™ XL) SiliconDioxide 0.500 0.600 (SYLOID ® 244FP) Glyceryl Behenate 1.500 1.800(COMPRITOL ®) Purified water^(b) N/A N/A Total 100% 120.0 mg FILM COATEDTABLET COMPOSITION INGREDIENT WEIGHT/WEIGHT %^(c) mg/TABLET^(d) PEG14503 0.1080 Hypromellose E5 97 3.492 (Premium LV) Purified water N/A N/ATotal 100% 123.6 mg ^(a)Atrasentan monohydrochloride salt factor = 1.07(i.e., 0.50 mg free base × 1.07 = 0.5350 mg salt). ^(b)Granulationsuspension medium. Less than 2% present in final product. ^(c)Based onan aqueous solution of 10% solids. ^(d)Based on a 120 mg tablet weightwith a coating weight gain of 3%.

TABLE 2-C Phase IIb Tablet (0.75 mg) TABLET CORE COMPOSITION INGREDIENTWEIGHT/WEIGHT % mg/TABLET Atrasentan 0.6690 0.8025^(a) MonohydrochlorideLactose Monohydrate 90.83 109.0 (Regular) Hypromellose E5 3.000 3.600(Premium LV) Crospovidone 3.500 4.200 (POLYPLASDONE ™ XL) SiliconDioxide 0.500 0.600 (SYLOID ® 244FP) Glyceryl Behenate 1.500 1.800(COMPRITOL ®) Purified water^(b) N/A N/A Total 100% 120.0 mg FILM COATEDTABLET COMPOSITION INGREDIENT WEIGHT/WEIGHT %^(c) mg/TABLET^(d) PEG14503 0.1080 Hypromellose E5 97 3.492 (Premium LV) Purified water N/A N/ATotal 100% 123.6 mg ^(a)Atrasentan monohydrochloride salt factor = 1.07(i.e., 0.75 mg free base × 1.07 = 0.8025 mg salt). ^(b)Granulationsuspension medium. Less than 2% present in final product. ^(c)Based onan aqueous solution of 10% solids. ^(d)Based on a 120 mg tablet weightwith a coating weight gain of 3%.

The 0.35 mg, 0.50 mg, and 0.75 mg Phase IIb tablets described above weretested for stability under one or more of the following storageconditions:

(a) Storage at 40° C. and 75% relative humidity with tablet stabilityassessed at the end of 1, 3, and 6 months (accelerated stability testingprotocol);

(b) Storage at 30° C. and 65% relative humidity with tablet stabilityassessed at the end of 12 months (intermediate-term stability testingprotocol); and

(c) Storage at 25° C. and 60% relative humidity with tablet stabilityassessed at the end of 1, 3, 6, 9, 12, 18, and 24 months (long-termstorage stability testing protocol).

In each stability test, 20 tablets were placed in a high-densitypolyethylene (“HDPE”) bottle containing a desiccant and the HDPE bottlewas induction-sealed with a polypropylene cap. Parameters measured forthe tablets at each time interval included atrasentan content relativeto labeled dose (assay), degradation product content, water content, anddissolution profile. The results are reported below in Tables 2-Dthrough 2-K. The “Assay” data reported represent the weight percent ofatrasentan measured relative to the labeled dose (i.e., either 0.35 mg,0.50 mg, or 0.75 mg). The “Degradation Products” data reported representthe weight percent of impurities measured relative to the labeled dose(i.e., either 0.35 mg, 0.50 mg, or 0.75 mg). All data reported representsingle values from single runs with the following exceptions: (a) theinitial atrasentan content value reported is a mean value where n=2, and(b) the dissolution values reported are mean values where n=6.

TABLE 2-D Storage Stability Under Accelerated Conditions (0.35 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 1 MONTH 3MONTHS MONTHS Description Physical Inspection Meets Meets requirementsMeets Meets requirements requirements requirements Appearance TabletTablet Tablet Tablet Marking Unmarked Unmarked Unmarked Unmarked ShapeRound Round Round Round Color White Off-white Off-white Off-whiteCoating Coated Coated Coated Coated Assay Assay 101.4/102.1 101.9 100.6100.0 Water Content Moisture 4.8 4.9 4.8 4.6 Dissolution 15 min: Mean 9594 93 96 30 min: Mean 100 100 99 100 45 min: Mean 100 100 100 100 60min: Mean 100 101 99 100 Degradation Total % Reported 0.11 0.10 0.340.33 Products ¹Note: Tablets stored in 3 oz HDPE bottle containing 1.1 gsilica desiccant and having induction sealed cap.

TABLE 2-E Storage Stability Under Long-Term Conditions (0.35 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 1 MONTH 3MONTHS 6 MONTHS Description Physical Inspection Meets Meets requirementsMeets Meets requirements requirements requirements Appearance TabletTablet Tablet Tablet Marking Unmarked Unmarked Unmarked Unmarked ShapeRound Round Round Round Color White Off-white Off-white Off-whiteCoating Coated Coated Coated Coated Assay Assay 101.4/102.1 101.4 100.8100.2 Water Content Moisture 4.8 4.7 4.6 4.4 Dissolution 15 min: Mean 9599 96 99 30 min: Mean 100 101 101 102 45 min: Mean 100 101 100 101 60min: Mean 100 100 101 101 Degradation Total % Reported 0.11 0.13 0.190.00 Products

TABLE 2-E (Continued): Storage Stability Under Long-Term Conditions(0.35 mg Phase IIb Tablet) SPECIFICATION¹ Acceptance 12 18 Test Criteria9 MONTH MONTHS MONTHS Description Physical Meets Meets Meets Inspectionrequirements requirements requirements Appearance Tablet Tablet TabletMarking Unmarked Unmarked Unmarked Shape Round Round Round ColorOff-white Off-white Off-white Coating Coated Coated Coated Assay Assay100.7 100.6 100.1 Water Moisture 4.5 4.9 4.7 Content Dissolution 15 min:Mean 96 96 91 30 min: Mean 101 102 95 45 min: Mean 101 103 98 60 min:Mean 101 102 98 Degradation Total % 0.10 0.21 0.0 Products Reported¹Note: Tablets stored in 3 oz HDPE bottle containing 1.1 g silicadesiccant and having induction sealed cap.

TABLE 2-F Storage Stability Under Accelerated Conditions (0.50 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 1 MONTH 3MONTHS 6 MONTHS Description Appearance Tablet Tablet Tablet TabletMarking Unmarked Unmarked Unmarked Unmarked Shape Round Round RoundRound Color Off-white Off-white White Off-white Coating Coated CoatedCoated Coated Assay Assay 98.6/99.0 97.6 96.7 93.6 Mean 98.8 — — — WaterContent Moisture 4.8 5.1 5.0 5.3 Dissolution 15 min: Mean 79 67 62 54 30min: Mean 93 92 89 81 45 min: Mean 95 97 93 84 60 min: Mean 96 98 94 85Degradation Total % 0 0.12 1.3 1.4 Products Reported ¹Note: Tabletsstored in 5 oz HDPE bottle containing 2 g clay desiccant and havinginduction sealed cap.

TABLE 2-G Storage Stablity Under Intermediate Conditions (0.50 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 12 MONTHS 15MONTHS 18 MONTHS Description Appearance Tablet Tablet Tablet TabletMarking Unmarked Unmarked Unmarked Unmarked Shape Round Round RoundRound Color Off-white Off-white Off-white Off-white Coating CoatedCoated Coated Coated Assay Assay 98.6/99.0 98.4 97.3 96.8 Mean 98.8 — —— Water Content Moisture 4.8 4.8 5.1 5.1 Dissolution 15 min: Mean 79 7876 80 30 min: Mean 93 93 91 87 45 min: Mean 95 95 93 93 60 min: Mean 9696 95 93 Degradation Total % 0 0.50 0.66 1.1 Products Reported ¹Note:Tablets stored in 5 oz HDPE bottle containing 2 g clay desiccant andhaving induction sealed cap.

TABLE 2-H Storage Stability Under Long-Term Conditions (0.50 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 1 MONTH 3MONTHS 6 MONTHS Description Appearance Tablet Tablet Tablet TabletMarking Unmarked Unmarked Unmarked Unmarked Shape Round Round RoundRound Color Off-white Off-white White Off-white Coating Coated CoatedCoated Coated Assay Assay 98.6/99.0 98.1 98.2 99.5 Mean 98.8 — — — WaterContent Moisture 4.8 4.7 5.0 5.1 Dissolution 15 min: Mean 79 82 83 75 30min: Mean 93 94 95 92 45 min: Mean 95 95 97 94 60 min: Mean 96 97 98 94Degradation Total % 0 0 0.69 0.22 Products Reported SPECIFICATION¹ Test9 MONTHS 12 MONTHS 18 MONTHS 24 MONTHS Description Appearance TabletTablet Tablet Tablet Marking Unmarked Unmarked Unmarked Unmarked ShapeRound Round Round Round Color Off-white Off-white Off-white Off-whiteCoating Coated Coated Coated Coated Assay Assay 100.5 99.1 98.2 95.3Mean — — — Water Content Moisture 4.7 4.7 4.9 5.0 Dissolution 15 min:Mean 74 77 79 76 30 min: Mean 95 93 92 91 45 min: Mean 98 95 96 93 60min: Mean 99 95 97 95 Degradation Total % 0.13 0.13 0.21 1.1 ProductsReported SPECIFICATION¹ Test 30 MONTHS 36 MONTHS Description AppearanceTablet Tablet Marking Unmarked Unmarked Shape Round Round ColorOff-white Off-White Coating Coated Coated Assay Assay 98.8 96.3 Mean — —Water Content Moisture 5.1 5.1 Dissolution 15 min: Mean 82 83 30 min:Mean 93 91 45 min: Mean 94 93 60 min: Mean 96 95 Degradation Total %Reported 0.91 0.85 Products ¹Note: Tablets stored in 5 oz HDPE bottlecontaining 2 g clay desiccant and having induction sealed cap.

TABLE 2-I Storage Stability Under Accelerated Conditions (0.75 mg PhaseIIb Tablet) Specification Acceptance Test Criteria Initial 1 Months 3Months 6 Months Description Appearance Tablet Tablet Tablet TabletMarking Unmarked Unmarked Unmarked Unmarked Shape Round Round RoundRound Color Off-white Off-white Off-white White Coating Coated CoatedCoated Coated Assay Assay 100.9/102.7 100.2 97.9 96.4 Mean 101.8 — — —Water Content Moisture 4.9 4.5 4.8 5.3 Dissolution 15 min: Mean 72 50 4047 30 min: Mean 96 93 84 84 45 min: Mean 96 98 92 91 60 min: Mean 97 10093 93 Degradation Total % 0.00 0 0.51 1.8 Products Reported

TABLE 2-J Storage Stability Under Intermediate Conditions (0.75 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 12 MONTHSDescription Appearance Tablet Tablet Marking Unmarked Unmarked ShapeRound Round Color Off-white White Coating Coated Coated Assay Assay100.9/102.7 99.2 Mean 101.8 — Water Content Moisture 4.9 4.8 Dissolution15 min: Mean 72 61 30 min: Mean 96 92 45 min: Mean 96 96 60 min: Mean 9798 Degradation Total % Reported 0.00 0.46 Products ¹Note: Tablets storedin 5 oz HDPE bottle containing 2 g clay desiccant and having inductionsealed cap.

TABLE 2-K Storage Stability Under Long-Term Conditions (0.75 mg PhaseIIb Tablet) SPECIFICATION¹ Acceptance Test Criteria INITIAL 1 MONTH 3MONTHS 6 MONTHS Description Appearance Tablet Tablet Tablet TabletMarking Unmarked Unmarked Unmarked Unmarked Shape Round Round RoundRound Color Off-white Off-white Off-white White Coating Coated CoatedCoated Coated Assay Assay 100.9/102.7 100.4 102.5 98.9 Mean 101.8 — — —Water Content Moisture 4.9 4.8 4.7 5.2 Dissolution 15 min: Mean 72 71 6771 30 min: Mean 96 96 96 95 45 min: Mean 96 99 99 98 60 min: Mean 97 99100 99 Degradation Total % 0 0 0.69 0.22 Products ReportedSPECIFICATION¹ Acceptance Test Criteria 9 MONTHS 12 MONTHS 18 MONTHS 24MONTHS Description Appearance Tablet Tablet Tablet Tablet MarkingUnmarked Unmarked Unmarked Unmarked Shape Round Round Round Round ColorOff-white White White White Coating Coated Coated Coated Coated AssayAssay 99.7 97.4 100.9 100.3 Mean — — — — Water Content Moisture 4.7 4.84.8 4.5 Dissolution 15 min: Mean 71 59 57 60 30 min: Mean 93 94 95 93 45min: Mean 97 98 99 97 60 min: Mean 97 100 101 99 Degradation Total %Reported 0.28 0 0 0.24 Products SPECIFICATION¹ Acceptance Test Criteria30 MONTHS 36 MONTHS Description Appearance Tablet Tablet MarkingUnmarked Unmarked Shape Round Round Color Off-white White Coating CoatedCoated Assay Assay 99.4 97.9 Mean Water Content Moisture 4.7 5.2Dissolution 15 min: Mean 70 62 30 min: Mean 91 91 45 min: Mean 94 93 60min: Mean 95 95 Degradation Total % Reported 0.70 0.58 Products ¹Note:Tablets stored in 5 oz HDPE bottle containing 2 g clay desiccant andhaving induction sealed cap.

In general, the stability data for the Phase IIb tablets indicate anincrease in atrasentan degradation products over a six month period atthe 40° C. and 75% relative humidity storage conditions for the 0.50 mgand 0.75 mg tablets.

Example 3 Effect of Anti-Oxidant on Stability

A study was conducted to evaluate the effect of an anti-oxidant onpreventing atrasentan degradation in a mixture of atrasentan, adisintegrant, and an anti-oxidant. Binary or tertiary mixturescontaining atrasentan monohydrochloride, a crospovidone disintegrant(POLYPLASDONE™ XL), and, for the tertiary mixtures, an anti-oxidant(selected from ascorbic acid powder, sodium metabisulfite, andL-cysteine hydrochloride monohydrate) at five different molar ratios ofatrasentan to anti-oxidant were prepared. In each case, the weight ratioof disintegrant to atrasentan was held constant at about 9:1. Thecompositions of the mixtures are shown below in Table 3-A (ascorbic acidpowder), Table 3-B (sodium metabisulfite), and Table 3-C (L-cysteinehydrochloride monohydrate). The mixtures were not further formulated(i.e., they were not processed into tablets or capsules) and weremaintained as loose blends of the components during storage. To ensurethat content non-uniformity for a single mixture did not impact theresults, several mixtures were prepared for each molar ratio tested anda different mixture was sampled and tested at each time point.

The mixtures were tested for stability using an accelerated stabilitytesting protocol under which each sample was stored in a 20 mL glassscintillation vial at 80° C. and ambient relative humidity. Stabilitywas assessed at initiation of testing, the end of seven days, and theend of three weeks. Stability testing results are reported below inTables 3-A through 3-F. All data reported represent single values fromsingle runs (i.e., n=1). The “Impurities” data reported below in Tables3-A through 3-C represent the percent impurities by HPLC peak areapercent. The “Weight % Atrasentan” data reported below in Tables 3-Dthrough 3-F represent the weight percent of atrasentan measured relativeto the corresponding weight of atrasentan initially added to themixture.

TABLE 3-A L-Ascorbic Acid Mixtures (Impurities) AMOUNT IMPURITIES (mg)(% BY PEAK AREA) MOLAR Anti- 7 3 RATIO^(a,b) Crospovidone AtrasentanOxidant Initial Days Weeks 1:0 455.03 50.17 0 0 0.97 2.9 435.07 52.08444.33 53.85 40:1  450.24 49.75 0.488 0 1.07 4.32 457.36 51.01 0.752467.29 50.92 0.539 10:1  463.96 48.18 2.42 0 0.98 1.72 457.52 49.481.740 434.63 49.65 1.290 5:1 438.28 48.77 3.348 0 1.23 4.36 434.40 49.652.964 443.74 54.72 3.297 1:1 453.68 51.81 16.205 0 1.19 2.51 439.0549.87 15.713 450.89 49.87 15.645 ^(a)Molar ratio ofAtrasentan:anti-oxidant. ^(b)Weight ratio of disintegrant:atrasentanheld constant at 9:1 for all samples.

TABLE 3-B Sodium Metabisulfite Mixtures (Impurities) AMOUNT IMPURITIES(mg) (% BY PEAK AREA) MOLAR Anti- 7 3 RATIO^(a,b) CrospovidoneAtrasentan Oxidant Initial Days Weeks 1:0 445.62 50.99 0 0 1.32 1.35433.54 50.24 461.37 51.51 40:1  436.67 51.35 0.648 0 0.15 0.81 446.0751.19 0.388 452.95 48.59 0.591 10:1  452.39 48.62 1.741 0.32 0.0 0.48467.67 49.21 1.548 440.83 50.20 1.818 5:1 438.55 50.93 3.785 1.05 0.320.58 452.75 50.21 3.469 459.80 52.16 3.050 1:1 453.75 53.82 15.649 4.903.32 7.62 437.94 53.65 14.883 454.18 54.87 15.041 ^(a)Molar ratio ofatrasentan:anti-oxidant. ^(b)Weight ratio of disintegrant:atrasentanheld constant at 9:1 for all samples.

TABLE 3-C L-Cysteine Mixtures (Impurities) AMOUNT IMPURITIES (mg) (% BYPEAK AREA) MOLAR Anti- 7 3 RATIO^(a,b) Crospovidone Atrasentan OxidantInitial Days Weeks 1:0 451.69 52.28 0 0 0.76 5.02 453.62 50.92 440.5351.27 40:1  456.22 51.09 0.485 0 0.72 2.99 459.97 52.04 0.680 443.5048.93 0.410 10:1  439.41 48.93 1.317 0 0.47 0.81 440.02 49.67 1.612438.98 47.98 1.410 5:1 436.56 54.65 2.825 0 0.32 0.46 445.34 50.17 2.880432.66 51.04 2.752 1:1 454.25 48.03 13.310 0 0.0 0.0 462.93 53.19 13.005454.65 54.11 14.603 ^(a)Molar ratio of atrasentan:anti-oxidant.^(b)Weight ratio of disintegrant:atrasentan to held constant at 9:1 forall samples.

TABLE 3-D L-Ascorbic Acid Mixtures (Atrasentan) AMOUNT WEIGHT % (mg)ATRASENTAN MOLAR Anti- 7 3 RATIO^(a,b) Crospovidone Atrasentan OxidantInitial Days Weeks 1:0 455.03 50.17 0 102.9 100.9 98.3 435.07 52.08444.33 53.85 40:1  450.24 49.75 0.488 104.4 101.0 98.1 457.36 51.010.752 467.29 50.92 0.539 10:1  463.96 48.18 2.42 103.7 102.0 97.3 457.5249.48 1.740 434.63 49.65 1.290 5:1 438.28 48.77 3.348 102.5 100.7 97.7434.40 49.65 2.964 443.74 54.72 3.297 1:1 453.68 51.81 16.205 102.9100.4 95.5 439.05 49.87 15.713 450.89 49.87 15.645 ^(a)Molar ratio ofAtrasentan:anti-oxidant. ^(b)Weight ratio of disintegrant:atrasentanheld constant at 9:1 for all samples.

TABLE 3-E Sodium Metabisulfite Mixtures (Atrasentan) AMOUNT WEIGHT %(mg) ATRASENTAN MOLAR Anti- 7 3 RATIO^(a,b) Crospovidone AtrasentanOxidant Initial Days Weeks 1:0 445.62 50.99 0 101.6 98.8 97.9 433.5450.24 461.37 51.51 40:1  436.67 51.35 0.648 101.8 101.0 98.5 446.0751.19 0.388 452.95 48.59 0.591 10:1  452.39 48.62 1.741 100.6 101.3 99.6467.67 49.21 1.548 440.83 50.20 1.818 5:1 438.55 50.93 3.785 99.9 101.399.3 452.75 50.21 3.469 459.80 52.16 3.050 1:1 453.75 53.82 15.649 99.296.1 86.9 437.94 53.65 14.883 454.18 54.87 15.041 ^(a)Molar ratio ofatrasentan:anti-oxidant. ^(b)Weight ratio of disintegrant:atrasentanheld constant at 9:1 for all samples.

TABLE 3-F L-Cysteine Mixtures (Atrasentan) AMOUNT WEIGHT % (mg)ATRASENTAN MOLAR Anti- 7 3 RATIO^(a,b) Crospovidone Atrasentan OxidantInitial Days Weeks 1:0 451.69 52.28 0 101.6 101.4 97.4 453.62 50.92440.53 51.27 40:1  456.22 51.09 0.485 101.8 100.7 98.3 459.97 52.040.680 443.50 48.93 0.410 10:1  439.41 48.93 1.317 101.3 100.2 99.7440.02 49.67 1.612 438.98 47.98 1.410 5:1 436.56 54.65 2.825 100.7 100.399.5 445.34 50.17 2.880 432.66 51.04 2.752 1:1 454.25 48.03 13.310 101.8101.4 101.3 462.93 53.19 13.005 454.65 54.11 14.603 ^(a)Molar ratio ofatrasentan:anti-oxidant. ^(b)Weight ratio of disintegrant:atrasentanheld constant at 9:1 for all samples.

In general, the stability data for the Phase IIb tablets indicate thatL-cysteine hydrochloride monohydrate provides the greatest stabilizingeffect of the three anti-oxidants, an interesting result given therelative oxidation reduction potentials (“ORP”) of the threeanti-oxidants. Atrasentan has an ORP value greater than about 900 mV.Ascorbic acid, sodium metabisulfite, and L-cysteine have ORP values ofabout 100-280 mV, about 175-300 mV, and about 815-965 mV, respectively.Although L-cysteine has an ORP value that is relatively close to the ORPvalue of atrasentan (indicating the least oxidative reactivity of theanti-oxidants tested with respect to atrasentan), it still provided thegreatest stabilizing effect.

Example 4 Effect of Atrasentan/L-Cysteine Molar Ratio on TabletStability

A study was conducted to evaluate the effect of molar ratio ofatrasentan to L-cysteine on atrasentan degradation in uncoated tabletscomprising L-cysteine hydrochloride monohydrate, but otherwisesubstantially the same as the tablet core composition described in Table2-B of Example 2. The tablets tested had the compositions shown inTables 4-A (2:1 molar ratio), 4-B (1:1 molar ratio), and 4-C (1:2 molarratio) below. The tablets were prepared using a wet granulation processand were compressed into round tablets having a core weight of 120 mgand a diameter of 6.5 mm.

TABLE 4-A L-Cysteine Tablet (2:1 Molar Ratio) WEIGHT/ INGREDIENT WEIGHT% mg/TABLET Atrasentan Monohydrochloride 0.31 0.372^(a) LactoseMonohydrate (Regular) 91.14 109.4 L-Cysteine Hydrochloride Monohydrate0.050 0.060 Hypromellose E5 (Premium LV) 3.000 3.600 Crospoyidone(POLYPLASDONE ™ XL) 3.500 4.200 Silicon Dioxide (SYLOID ® 244FP) 0.5000.600 Glyceryl Behenate (COMPRITOL ®) 1.500 1.800 Purified water^(b) N/AN/A Total 100% 120.0 mg ^(a)Atrasentan monohydrochloride salt factor =1.07 (i.e., 0.31 mg free base × 1.07 = 0.372 mg salt). ^(b)Granulationsuspension medium. Less than 2% present in final product.

TABLE 4-B L-Cysteine Tablet (1:1 Molar Ratio) WEIGHT/ INGREDIENT WEIGHT% mg/TABLET Atrasentan Monohydrochloride 0.31 0.372^(a) LactoseMonohydrate (Regular) 91.09 109.3 L-Cysteine Hydrochloride Monohydrate0.0999 0.120 Hypromellose E5 (Premium LV) 3.000 3.600 Crospovidone(POLYPLASDONE ™ XL) 3.500 4.200 Silicon Dioxide (SYLOID ® 244FP) 0.5000.600 Glyceryl Behenate (COMPRITOL ®) 1.500 1.800 Purified water^(b) N/AN/A Total 100% 120.0 mg ^(a)Atrasentan monohydrochloride salt factor =1.07 (i.e., 0.31 mg free base × 1.07 = 0.372 mg salt). ^(b)Granulationsuspension medium. Less than 2% present in final product.

TABLE 4-C L-Cysteine Tablet (1:2 Molar Ratio) WEIGHT/ INGREDIENT WEIGHT% mg/TABLET Atrasentan Monohydrochloride 0.31 0.372^(a) LactoseMonohydrate (Regular) 91.07 109.2 L-Cysteine Hydrochloride Monohydrate0.200 0.240 Hypromellose E5 (Premium LV) 3.000 3.600 Crospovidone(POLYPLASDONE ™ 3.500 4.200 XL) Silicon Dioxide (SYLOID ® 244FP) 0.5000.600 Glyceryl Behenate (COMPRITOL ®) 1.500 1.800 Purified water^(b) N/AN/A Total 100% 120.0 mg ^(a)Atrasentan monohydrochloride salt factor =1.07 (i.e., 0.31 mg free base × 1.07 = 0.372 mg salt). ^(b)Granulationsuspension medium. Less than 2% present in final product.

The tablets described above were tested for stability using anaccelerated stability testing protocol. The tablets were packaged in 3ounce HDPE bottles with induction sealed caps and stored at 50° C. andambient relative humidity. Each bottle contained 20 tablets and 1.1 g ofa silica desiccant. Tablet stability was assessed at the end of 3, 6,and 9 weeks. The stability testing results are reported below in Table4-D. The “Assay” data reported represent the weight percent ofatrasentan measured relative to the labeled dose (i.e., 0.31 mg). Alldata reported represent single values from single runs (n=1).

TABLE 4-D Stability Test Results For L-Cysteine Tablets MOLAR WEIGHT %ATRASENTAN RATIO^(a) INITIAL 3 WEEKS 6 WEEKS 9 WEEKS 2:1 95.4% 95.2%93.9% 92.9% 1:1 99.3% 98.3% 98.2% 98.7% 1:2 99.9% 98.6% 99.1% 98.6%^(a)Molar ratio of atrasentan:anti-oxidant.

Example 5 Effect of HPMC on Tablet Stability (Lab Scale)

A lab-scale study (i.e., each batch prepared was less than 500 mg) wasconducted to evaluate the effect of HPMC on atrasentan tablet stability.Uncoated tablets corresponding to the compositions shown in Table 5-Abelow were prepared at a drug loading of 0.45% (based on the weight ofatrasentan monohydrochloride) using five different methods ofpreparation that differed in the manner atrasentan was treated with theHPMC.

TABLE 5-A HPMC Tablet WEIGHT/ INGREDIENT WEIGHT % mg/TABLET AtrasentanMonohydrochloride 0.449 0.54^(a) Lactose Monohydrate (Regular) 91.05109.3 Hypromellose E5 (Premium LV) 3.000 3.600 Crospovidone(POLYPLASDONE ™ XL) 3.500 4.200 Silicon Dioxide (SYLOID ®) 0.500 0.600Glyceryl Behenate (COMPRITOL ®) 1.500 1.800 Purified water^(b) N/A N/ATotal 100% 120 mg ^(a)Atrasentan monohydrochloride salt factor = 1.07.^(b)Granulation suspension medium. Less than 2% present in finalproduct.

Method of Preparation 1 (Wet Granulation with HPMC/Atrasentan Solution):

Atrasentan was completely dissolved in a 9% HPMC solution. All otheringredients were added to a granulation bowl in dry form. Theatrasentan/HPMC solution was sprayed into the granulation bowl and theingredients were wet granulated using a lab-scale key granulator. Thegranulated mixture was tray-dried in an oven without vacuum and thencompressed into tablets that were left uncoated.

Method of Preparation 2 (Wet Granulation with HPMC/AtrasentanSuspension):

Atrasentan was added to a 9% HPMC solution to form a suspension. Allother ingredients were added to a granulation bowl in dry form. Theatrasentan/HPMC suspension was sprayed into the granulation bowl and theingredients were wet granulated using lab-scale key granulator. Thegranulated mixture was tray-dried in an oven without vacuum and thencompressed into uncoated tablets.

Method of Preparation 3 (Direct Blend: Dry Mix):

Atrasentan was dry mixed with HPMC. The atrasentan/HPMC mixture was thenmixed with the remaining ingredients in dry form and without theaddition of water or any other liquid. The mixed ingredients weredirectly compressed into tablets that were left uncoated.

Method of Preparation 4 (Direct Blend: Dry Granulation):

Atrasentan was compressed with HPMC (dry granulation) and sieved toprovide atrasentan/HPMC dry granules. The atrasentan/HPMC dry granuleswere then mixed with the remaining ingredients in dry form and withoutthe addition of water or any other liquid. The mixed ingredients weredirectly compressed into tablets that were left uncoated.

Method of Preparation 5 (Direct Blend: No Pre-Treatment):

Atrasentan, HPMC, and the other ingredients were mixed in dry formwithout any pre-treatment of the atrasentan with HPMC and without theaddition of water or any other liquid. The mixed ingredients weredirectly compressed into tablets that were left uncoated.

In all cases, the final mixture was manually compressed into 1 g tabletsusing a Carver Press.

The tablets described above were tested for stability using anaccelerated stability testing protocol under which the tablets werestored at 50° C. and 75% relative humidity in sealed, 5 oz., HDPEbottles containing 2 g of a clay desiccant. Tablet stability wasassessed at the initiation of testing and at the end of three, six, andeight weeks. Stability testing results are reported below in Table 6-B.The “Impurities” data reported represent the percent impurities by HPLCpeak area percent. All data reported represent single values from singleruns (n=1).

TABLE 5-B Stability Test Results IMPURITIES (% BY PEAK AREA) METHODInitial 3 Weeks 6 Weeks 8 Weeks 1 3.8 5.6 5.8 6.5 2 4.2 5.7 7.1 7.1 32.7 3.9 3.7 3.8 4 3.4 5.2 4.7 4.6 5 3.8 4.8 5.2 5.7

The data indicate that pre-treatment of atrasentan with HPMC during thepreparation of the direct blend tablets (i.e., dry-mixed tabletsprepared in Method 3 or dry-granulated tablets prepared as in Method 4)reduces total impurities relative to direct blend tablets preparedwithout any pre-treatment of atrasentan with HPMC (i.e., dry-mixing asin Method 5).

The data for the wet-granulated tablets prepared as in Method 1 orMethod 2 indicate a higher impurity content than is typically observedfor wet-granulated tablets prepared in larger scale operations (seeExample 6 below). It is believed that the higher impurities content isattributable to factors such as the use of lab-scale equipment (e.g.,tray-drying in an oven without vacuum rather than vacuum drying) and theuse of lower-grade excipients than typically required for thepreparation of clinical and commercial tablets.

Example 6 Effect of HPMC on Tablet Stability (Manufacturing Scale)

A manufacturing-scale study (i.e., each batch prepared was at leastabout 15 kg) was conducted to evaluate the effect of HPMC on atrasentantablet stability. Uncoated tablets corresponding to the compositionsshown in Table 6-A below were prepared at three different drug loadings(0.05%, 0.17%, and 0.27%) using three different methods of preparationas described below.

TABLE 6-A HPMC Tablet WEIGHT/ INGREDIENT WEIGHT % mg/TABLET AtrasentanMonohydrochloride 0.05-0.27 0.05-0.27^(a) Lactose Monohydrate (Regular)Quantity Quantity Sufficient Sufficient Hypromellose E5 (Premium LV)3.000 3.000 Crospovidone (POLYPLASDONE ™ XL) 3.500 3.500 Silicon Dioxide(SYLOID ®) 0.500 0.500 Glyceryl Behenate (COMPRITOL ®) 1.500 1.500Purified water^(b) N/A N/A Total 100% 100 mg ^(a)Atrasentanmonohydrochloride salt factor = 1.07. ^(b)Granulation suspension medium.Less than 2% present in final product.

Method of Preparation 1 (Direct Blend):

All ingredients were mixed in dry form without the addition of water orany other liquid. The mixed ingredients were directly compressed intotablets that remained uncoated for stability testing.

Method of Preparation 2 (Wet Granulation with HPMC Solution):

All ingredients except HPMC were added dry to a granulation bowl andwere wet granulated using a 9% HPMC solution. The granulated mixture wasdried under vacuum and then compressed into uncoated tablets.

Method of Preparation 3 (Wet Granulation with HPMC/AtrasentanSuspension):

Atrasentan was added to a 9% HPMC solution to form a suspension. Allother ingredients were added to a granulation bowl in dry form. Thesuspension was sprayed into the granulation bowl and the ingredientswere wet granulated. The granulated mixture was dried under vacuum andthen compressed into tablets that remained uncoated for stabilitytesting.

The tablets described above were tested for stability using anaccelerated stability testing protocol under which 20 tablets werestored at 50° C. and 75% relative humidity in a sealed, 3 oz., HDPEbottle containing 2 g of a clay desiccant. Tablet stability was assessedat the initiation of testing and at the end of two and four weeks.Stability testing results are reported below in Table 6-A (Method 1),Table 6-B (Method 2), and Table 6-C (Method 3). The “Impurities” datareported represent the percent impurities by HPLC peak area percent. Alldata reported represent single values from single runs (i.e., n=1).

TABLE 6-B Stability Test Results (Method 1) DRUG IMPURITIES (% BY PEAKAREA) LOADING (%) Initial 2 Weeks 4 Weeks 0.05 0.30 1.61 2.52 0.17 NotTested Not Tested Not Tested 0.27 Not Tested Not Tested Not Tested

TABLE 6-C Stability Test Results (Method 2) IMPURITIES DRUG (% BY PEAKAREA) LOADING (%) Initial 2 Weeks 4 Weeks 0.05 1.23 2.13 2.52 0.17 NR0.59 0.98 0.27 0.39 1.68 2.91

TABLE 6-D Stability Test Results (Method 3) IMPURITIES DRUG (% BY PEAKAREA) LOADING (%) Initial 2 Weeks 4 Weeks 0.05 0.76 1.08 1.26 0.17 NR0.67 0.68 0.27 0.13 0.32 0.55

Although there was no discernible difference in content uniformitybetween the tablets prepared by Method 2 (atrasentan added dry to thegranulation bowl prior to the addition of the HPMC solution) and thetablets prepared by Method 3 (atrasentan added to the granulation bowlas an HPMC/atrasentan suspension), the chemical degradation ofatrasentan over time was higher for the tablets prepared by Method 2than for the tablets prepared by Method 3. In addition, the rate ofchemical degradation of atrasentan for the tablets prepared by Method 1(atrasentan and HPMC added dry to the granulation bowl) was higher thanfor the corresponding tablets prepared by Method 2 (atrasentan added dryto the granulation bowl prior to the addition of the HPMC solution).

Example 7 Effect of HPMC on Spray-Coated Placebo Core Tablet Stability

A study was conducted to compare the effect of HPMC and Kollicoat (acopolymer of polyvinyl alcohol) on atrasentan tablet stability.Atrasentan was dissolved or suspended (depending upon drug loading) in apolymer coating solution to form an atrasentan/polymer coating solution.In each case, a placebo core having the composition shown in Table 7-Awas sprayed with a polymer base coating, then the atrasentan/polymercoating, and finally a polymer seal coat. The atrasentan/polymercoating, polymer base coating, and polymer seal coating had thecompositions shown in Table 7-B (HPMC/0.05 mg atrasentan), Table7-C(HPMC/0.75 mg atrasentan), Table 7-D (Kollicoat/0.05 mg atrasentan),and Table 7-E (Kollicoat/0.55 mg atrasentan).

TABLE 7-A Placebo Core Tablet PLACEBO CORE TABLET COMPOSITION INGREDIENTWEIGHT/WEIGHT % mg/TABLET Avicel PH 102 46.6 116.25 Lactose MonohydrateFastFlo 46.5 116.25 Sodium Stearyl Fumarate 2 5 Croscarmellose Sodium 25 Hydroxypropyl Cellulose 3 7.5 Total 100% 250 mg

TABLE 7-B HPMC/Atrasentan Coating (0.055 mg) INGREDIENT WEIGHT/WEIGHT %mg/TABLET ATRASENTAN/POLYMER COATING Atrasentan Monohydrochloride 0.0220.055^(a) Hydroxypropylemethylcellulose 8.0 19.92 (Methocel E5) POLYMERBASE AND SEAL COATING^(b) Hydroxypropylmethylcellulose 9.7 9.7 (MethocelE5) Polyethylene Glycol 1450 0.3 0.3 ^(a)Atrasentan monohydrochloridesalt factor = 1.07 (i.e., 0.05 mg free base × 1.07 = 0.055 mg salt).^(b)The polymer base coat was sprayed on the placebo core for atheoretical weight gain of 2% and the polymer seal coat was sprayed ontop of the atrasentan/polymer coating layer theoretical weight gain of2%. The combined theoretical weight gain attributable to the polymerbase and seal coats was 4%.

TABLE 7-C HPMC/Atrasentan Coating (0.79 mg) INGREDIENT WEIGHT/WEIGHT %mg/TABLET ATRASENTAN/POLYMER COATING Atrasentan Monohydrochloride 0.320.79^(a) Hydroxypropylmethylcellulose 8.2 20.56 (Methocel E5) POLYMERBASE AND SEAL COATING^(b) Hydroxypropylmethylcellulose 9.7 9.7 (MethocelE5) Polyethylene Glycol 1450 0.3 0.3 ^(a)Atrasentan monohydrochloridesalt factor = 1.07 (i.e., 0.75 mg free base × 1.07 = 0.79 mg salt).^(b)The polymer base coat was sprayed on the placebo core for atheoretical weight gain of 2% and the polymer seal coat was sprayed ontop of the atrasentan/polymer coating layer theoretical weight gain of2%. The combined theoretical weight gain attributable to the polymerbase and seal coats was 4%.

TABLE 7-D Kollicoat/Atrasentan Coating (0.055 mg) INGREDIENTWEIGHT/WEIGHT % mg/TABLET ATRASENTAN/POLYMER COATING AtrasentanMonohydrochloride 0.022 0.055^(a) Kollicoat IR 8.6 21.50 POLYMER BASEAND SEAL COATING^(b) Kollicoat IR 15 10 ^(a)Atrasentan monohydrochloridesalt factor = 1.07 (i.e., 0.05 mg free base × 1.07 = 0.055 mg salt).^(b)The polymer base coat was sprayed on the placebo core for atheoretical weight gain of 2% and the polymer seal coat was sprayed ontop of the atrasentan/polymer coating layer theoretical weight gain of2%. The combined theoretical weight gain attributable to the polymerbase and seal coats was 4%.

TABLE 7-E Kollicoat/Atrasentan Coating (0.59 mg) INGREDIENTWEIGHT/WEIGHT % mg/TABLET ATRASENTAN/POLYMER COATING AtrasentanMonohydrochloride 0.24 0.59^(a) Kollicoat IR 9.0 22.50 POLYMER BASE ANDSEAL COATING* Kollicoat IR 15 10 ^(a)Atrasentan monohydrochloride saltfactor = 1.07 (i.e., 0.55 mg free base × 1.07 = 0.59 mg salt). ^(b)Thepolymer base coat was sprayed on the placebo core for a theoreticalweight gain of 2% and the polymer seal coat was sprayed on top of theatrasentan/polymer coating layer theoretical weight gain of 2%. Thecombined theoretical weight gain attributable to the polymer base andseal coats was 4%.

The tablets prepared as described above were tested for stability usingan accelerated stability testing protocol under which 20 tablets werestored at 50° C. and 75% relative humidity in a sealed, 5 oz. HDPEbottles containing 2 g of a clay desiccant. Tablet stability wasassessed at the initiation of testing and at the end of two and fourweeks. Stability testing results are reported below in Table 7-F. The“Impurities” data reported represent the percent impurities by HPLC peakarea percent. All data reported represent single values from single runs(i.e., n=1).

TABLE 7-F Stability Test Results ATRASENTAN/POLYMER IMPURITIES (% BYPEAK AREA) COATING Initial 2 Weeks 4 Weeks HPMC/0.05 mg atrasentan 0.801.11 0.74 HPMC/0.75 mg atrasentan 0.17 0.22 0.24 Kollicoat/0.05 mgatrasentan 1.81 2.68 2.38 Kollicoat/0.50 mg atrasentan 0.69 1.87 1.60

Because degradation of atrasentan can be moisture-activated, theatrasentan-coated tablet approach of this Example is considered to be aproduct presentation that is more susceptible to atrasentan degradation.The results show improved chemical stability for the HPMC-coated tabletsrelative to the Kollicoat-coated tablets.

Example 8 Effect of HPMC on Atrasentan Solid State Behavior

The effect of HPMC on the solid state behavior of atrasentan wasevaluated in a study in which slurry samples of atrasentan Form IIpolymorph suspended in a 9% HPMC solution stored at room temperature and40° C. were compared with corresponding slurry samples obtained fromatrasentan Form II polymorph suspended in water stored at roomtemperature and 40° C. The atrasentan concentration in all foursuspensions was 4.4% by weight. Samples (1 mL) were taken from eachsuspension at 30 minutes, 6 hours, and 30 hour from initiation andcentrifuged to provide both a solid material and a filtrate for furtheranalysis.

The solid material from each sample was analyzed by powder x-raydiffraction (“PXRD”) and compared to the PXRD for the correspondinginitial sample (i.e., the PXRD pattern for the atrasentan Form IIpolymorph). Although the primary PXRD pattern for all suspensions after30 minutes and 6 hours at either room temperature or 40° C. stillcorresponded to the PXRD pattern for the atrasentan Form II polymorph,the PXRD pattern for the samples obtained from the suspensions withoutHPMC indicated partial conversion of the atrasentan Form II polymorph tothe more thermodynamically stable atrasentan Form I polymorph at bothroom temperature and 40° C. A higher level of conversion was seen forthe suspensions without HPMC stored at 40° C. The PXRD pattern for thesamples obtained from the suspensions with HPMC stored at roomtemperature showed no conversion of the atrasentan Form II polymorph tothe more thermodynamically stable atrasentan Form I polymorph at anytimepoint. The PXRD pattern for the samples obtained from thesuspensions with HPMC stored at 40° C. showed no conversion at the 6hour timepoint and only minimal conversion at the 30 hour timepoint.

The filtrates collected from the slurry samples at each time point werefreeze-dried by a lab scale lyophilizer. Prior to lyophilization of thefiltrate, the pH of the suspension was measured. The average pH was 1.8for filtrates from suspensions containing no HPMC and 2.2 forsuspensions with HPMC. The pH for each sample remained consistent,regardless of time or temperature. The freeze-dried filtrates weresubmitted for solid-state NMR analysis to determine if any chemicalinteraction between HPMC and atrasentan could be observed, but thesample concentrations were too dilute for analysis.

The results indicate that the presence of HPMC in the suspension: (a)slows and possibly prevents the conversion of atrasentan Form IIpolymorph to the more thermodynamically stable atrasentan Form Ipolymorph at room temperature, and (b) slows the conversion ofatrasentan Form II polymorph to the more thermodynamically stableatrasentan Form I polymorph at 40° C.

Example 9 Effect of HPMC on Atrasentan Surface Energy

Wet granulation blends prepared as described in Method 2 (atrasentanadded dry to granulation bowl) and Method 3 (atrasentan added as HPMCsuspension to granulation bowl) of Example 6 were analyzed prior tocompression using inverse gas chromatography (“IGC”) to determine thesurface energy of the blends. These measurements were compared to themeasured values for pure atrasentan and pure HPMC. The results are shownin Table 9 below.

TABLE 9 Surface Energy DISPERSIVE SURFACE ENERGY (mJ · m⁻²) StandardDeviation SAMPLE Run 1 Run 2 Average (%) HPMC E5 36.3 36.9 36.6 1.13Atrasentan 50.6 51.4 50.9 1.02 Monohydrochloride Method 1 Blend 47.946.5 47.2 2.24 Method 2 Blend 45.9 44.2 45.0 2.54

The results indicate that the blends lie closer in energy value to pureHPMC than to pure atrasentan (likely due to a larger concentration ofHPMC in the blend than atrasentan). The results further indicate thatthe wet granulation blend prepared as described in Method 2 (atrasentanadded dry to granulation bowl) has a higher surface energy than the wetgranulation blend prepared as described in Method 3 (atrasentan added asHPMC suspension to granulation bowl) which is consistent with the higheratrasentan degradation seen in the Method 2 blend compared to the Method3 blend (see Example 6).

Overall, the results of Examples 5 to 9 confirm that HPMC stabilizesatrasentan and reduces atrasentan degradation in the low-dose dosageforms of the present disclosure. This stabilizing effect is observedwhen atrasentan is intimately mixed with HPMC during the preparation ofthe dosage form, such as introducing atrasentan to the granulation bowlas an atrasentan/HPMC suspension or as a dry mixture of atrasentan andHPMC.

Example 10 Phase III Tablet Stability

Two atrasentan dosage forms having the compositions shown in Table 10-A(0.50 mg tablet) and Table 10-B (0.75 mg tablet) below were prepared foruse in Phase III clinical trials to evaluate the safety and efficacy ofatrasentan in treating subjects with diabetic nephropathy. The tabletswere prepared using a wet granulation process and were compressed intoround tablets having a core weight of 120 mg and a diameter of 6.5 mm. Athird atrasentan dosage form having the composition shown in Table 10-C(0.35 mg tablet) can be prepared in a similar manner. The 0.35 mgtablet, 0.50 mg tablet, and 0.75 mg tablet have drug loads (based onweight of atrasentan monohydrochloride) of 0.31%, 0.45%, and 0.67%,respectively.

TABLE 10-A Phase III Tablet (0.50 mg) TABLET CORE COMPOSITION WEIGHT/INGREDIENT WEIGHT % mg/TABLET Atrasentan Monohydrochloride 0.44600.5350^(a) Lactose Monohydrate (Regular) 90.91 109.1 L-CysteineHydrochloride Monohydrate 0.1440 0.1728 Hypromellose E5 (Premium LV)3.000 3.600 Crospovidone (POLYPLASDONE ™ XL) 3.500 4.200 Silicon Dioxide(SYLOID ® 244FP) 0.500 0.600 Glyceryl Behenate (COMPRITOL ®) 1.500 1.800Purified water N/A N/A Total 100% 120.0 mg FILM-COATED TABLETCOMPOSITION WEIGHT/ INGREDIENT WEIGHT %^(c) mg/TABLET^(d) PEG1450 3 0.1Hypromellose E5 (Premium LV) 97 3.5 Purified water N/A N/A Total 100%123.6 mg ^(a)Atrasentan monohydrochloride salt factor = 1.07 (i.e., 0.50mg free base × 1.07 = 0.5350 mg salt). ^(b)Granulation suspensionmedium. Less than 2% present in final product. ^(c)Based on an aqueoussolution of 10% solids. ^(d)Based on a 120 mg tablet weight with acoating weight gain of 3%.

TABLE 10-B Phase III Tablet (0.75 mg) TABLET CORE COMPOSITION WEIGHT/INGREDIENT WEIGHT % mg/TABLET Atrasentan Monohydrochloride 0.66900.8025^(a) Lactose Monohydrate (Regular) 90.61 108.7 L-cysteineHydrochloride Monohydrate 0.216 0.2592 Hypromellose E5 (Premium LV)3.000 3.600 Crospovidone (POLYPLASDONE ™ XL) 3.500 4.200 Silicon Dioxide(SYLOID ® 244FP) 0.500 0.600 Glyceryl Behenate (COMPRITOL ®) 1.500 1.800Purified water N/A N/A Total 100% 120.0 mg FILM-COATED TABLETCOMPOSITION WEIGHT/ INGREDIENT WEIGHT %^(c) mg/TABLET^(d) PEG1450 30.1080 Hypromellose E5 (Premium LV) 97 3.492 Purified water N/A N/ATotal 100% 123.6 mg ^(a)Atrasentan monohydrochloride salt factor = 1.07(i.e., 0.75 mg free base × 1.07 = 0.8025 mg salt). ^(b)Granulationsuspension medium. Less than 2% present in final product. ^(c)Based onan aqueous solution of 10% solids. ^(d)Based on a 120 mg tablet weightwith a coating weight gain of 3%.

TABLE 10-C 0.35 Tablet TABLET CORE COMPOSITION WEIGHT/ INGREDIENT WEIGHT% mg/TABLET Atrasentan Monohydrochloride 0.31 0.372^(a) LactoseMonohydrate (Regular) 91.09 109.3 L-Cysteine Hydrochloride 0.0999 0.120Monohydrate Hypromellose E5 (Premium LV) 3.00 3.6 Crospovidone(POLYPLASDONE ™ XL) 3.50 4.2 Silicon Dioxide (SYLOID ®) 0.50 0.6Glyceryl Behenate (COMPRITOL ®) 1.50 1.8 Purified water^(b) N/A N/ATotal 100% 120 mg FILM-COATED TABLET COMPOSITION WEIGHT/ INGREDIENTWEIGHT %^(c) mg/TABLET^(d) PEG1450 3 0.1 Hypromellose E5 (Premium LV) 973.5 Purified water N/A N/A Total 100% 123.6 mg ^(a)Atrasentanmonohydrochloride salt factor = 1.07 (i.e., 0.35 mg free base × 1.07 =0.37 mg salt). ^(b)Granulation suspension medium. Less than 2% presentin final product. ^(c)Based on an aqueous solution of 10% solids.^(d)Based on a 120 mg tablet weight with a coating weight gain of 3%.

Table 10A/B provides a comparison of the target composition for the 0.50mg and 0.75 mg Phase III tablets prepared in large-scale tabletingoperations.

TABLE 10A/B Comparison of 0.50 mg and 0.75 Tablets Dosage Strength 0.5mg 0.75 mg Amount (mg)/ Amount (mg)/ Component Tablet Tablet TABLET COREIntragranular Atrasentan HCl 0.54 0.81 Lactose Monohydrate 109.1 108.7Hypromellose 3.6 3.6 Crospovidone 4.2 4.2 Silicon Dioxide/ 0.3 0.3Silica, Anhydrous Cysteine Hydrochloride/ 0.2 0.3 Cysteine HydrochlorideMonohydrate Purified Water^(a) N/A N/A Extragranular SiliconDioxide/Silica, Anhydrous 0.3 0.3 Glyceryl Behenate/Glycerol Dibehenate1.8 1.8 FILM COATING^(B) Polyethylene Glycol 1450 0.1 0.1 Hypromellose3.5 3.5 Purified Water^(a) N/A N/A ^(a)Removed during processing^(B)Film coat weight is approximate N/A = Not applicable

The 0.50 mg and 0.75 mg Phase III tablets described above are tested forstability under each of the following storage conditions:

(a) Storage at 40° C. and 75% relative humidity with tablet stabilityassessed at the end of 1, 3, and 6 months (accelerated stability testingprotocol);

(b) Storage at 30° C. and 75% relative humidity with tablet stabilityassessed at the end of 12 months (intermediate-term stability testingprotocol A);

(c) Storage at 30° C. and 65% relative humidity with tablet stabilityassessed at the end of 12 months (intermediate-term stability testingprotocol B);

(d) Storage at 25° C. and 60% relative humidity with tablet stabilityassessed at the end of 1, 3, 6, 9, 12, 18, and 24 months (long-termstorage stability testing protocol A); and

(e) Storage at 40° C. and 75% relative humidity with tablet stabilityassessed at the end of 1, 3, 6, 9, 12, 18, and 24 months (long-termstorage stability testing protocol B).

In each stability test, 20 tablets are stored in a 3 oz HDPE bottlecontaining 1.1 g of a silica desiccant and having induction sealed cap.Parameters measured for the tablets at each time interval includeatrasentan content relative to the labeled dose, degradation productcontent, water content, and dissolution rate. The 0.35 mg dosage formshown in Table 10-C can be tested in a similar manner.

Stability data for the 0.50 mg Phase III tablet and the 0.75 mg PhaseIII tablet under the long-term storage protocols are reported in Tables10-D, 10-E, 10-F, and 10-G below.

TABLE 10-D Storage Stability Under Long-Term Conditions (25° C./60% RH)(0.50 mg Phase III Tablet) Specification Acceptance Test CriteriaInitial 1 Months 3 Month 6 Months 9 Months Description Appearance TabletTablet Tablet Tablet Tablet Marking Unmarked Unmarked Unmarked UnmarkedUnmarked Shape Round, Round, Round, Round, Round, Biconvex BiconvexBiconvex Biconvex Biconvex Color Off-White Off-White White WhiteOff-White Coating Coated Coated Coated Coated Coated Assay Assay 97.596.4 97.0 98.5 97.8 Mean Water Content Moisture 4.9 4.9 5.1 4.9 4.8L-Cysteine 63.6 60.3 56.3 53.6 50.3 Determination Dissolution 15 min:Mean 99 95 96 96 94 30 min: Mean 99 98 96 97 95 45 min: Mean 99 97 97 9795 60 min: Mean 99 98 96 96 95 Degradation Total % Reported ND ND ND NDND Products

TABLE 10-E Storage Stability Under Long-Term Conditions (25° C./60% RH)(0.75 mg Phase III Tablet) Specification Acceptance Test CriteriaInitial 1 Months 3 Month 6 Months Description Appearance Tablet TabletTablet Tablet Marking Unmarked Unmarked Unmarked Unmarked Shape Round,Round, Round, Round, Biconvex Biconvex Biconvex Biconvex Color Off-WhiteWhite White Off-White Coating Coated Coated Coated Coated Assay Assay96.9 96.9 94.9 96.8 Mean Water Content Moisture 4.7 4.4 4.7 4.6L-Cysteine 60.5 53.7 51.9 49.4 Determination Dissolution 15 min: Mean 9495 94 91 30 min: Mean 96 98 97 94 45 min: Mean 96 98 96 95 60 min: Mean96 98 97 95 Degradation Total % Reported ND ND ND ND Products

TABLE 10-F Storage Stability Under Long-Term Conditions (40° C./75% RH)(0.50 mg Phase III Tablet) Specification Acceptance Test CriteriaInitial 1 Months 3 Month 6 Months Description Appearance Tablet TabletTablet Tablet Marking Unmarked Unmarked Unmarked Unmarked Shape Round,Round, Round, Round, Biconvex Biconvex Biconvex Biconvex Color Off-WhiteOff-White White Off-White Coating Coated Coated Coated Coated AssayAssay 97.5 96.8 97.6 97.9 Mean Water Content Moisture 4.9 5.0 5.0 5.0L-Cysteine 63.6 52.2 37.1 18.4 Determination Dissolution 15 min: Mean 9992 81 77 30 min: Mean 99 99 95 97 45 min: Mean 99 97 96 97 60 min: Mean99 98 96 97 Degradation Total % ND ND ND ND Products Reported

TABLE 10-G Storage Stability Under Long-Term Conditions (40° C./75% RH)(0.75 mg Phase III Tablet) Specification Acceptance Test CriteriaInitial 1 Months 3 Month 6 Months Description Appearance Tablet TabletTablet Tablet Marking Unmarked Unmarked Unmarked Unmarked Shape Round,Round, Round, Round, Biconvex Biconvex Biconvex Biconvex Color Off-WhiteWhite White Pale yellow Coating Coated Coated Coated Coated Assay Assay96.9 95.2 95.4 96.7 Mean Water Content Moisture 4.7 4.7 4.8 4.9L-Cysteine 60.5 49.1 36.6 23.2 Determination Dissolution 15 min: Mean 9480 72 72 30 min: Mean 96 96 98 95 45 min: Mean 96 96 97 95 60 min: Mean96 96 97 94 Degradation Total % Reported ND ND 0.18 0.13 Products

Example 11 Packaged Tablet Stability

Stability of the 0.50 mg Phase IIb tablet (i.e., the tabletcorresponding to Table 2-B of Example 2) and the 0.50 mg Phase IIItablet (i.e., the tablet corresponding to Table 10-A of Example 10)packaged in several different configurations was tested. The packagingconfigurations tested included:

(a) tablets in a one ounce HDPE bottle containing 1.1 g of a silicadesiccant;

(b) tablet in an aluminum (Al) foil blister;

(c) tablet in an ACLAR® 3000 blister;

(d) tablet in an ACLAR® 4000 blister;

(e) tablets in an ACLAR® 4000 blister sealed in a foil overwrap with 1.1g of a silica desiccant; and

(f) tablets blistered in an ACLAR® Rx160 blister sealed in a foiloverwrap with 1.1 g of a silica desiccant.

The packaged tablets were tested for stability using an acceleratedstability testing protocol under which the tablets were stored at 40° C.and 75% relative humidity and tablet stability was assessed atinitiation of the testing and at the end of one, three, and six months.Accelerated stability testing results are reported below in Table 11.The “Assay” data reported represent the weight percent of atrasentanmeasured relative to the labeled dose (i.e., 0.50 mg). All data reportedrepresent single values from single runs (i.e., n=1).

TABLE 11 Packaged Tablets PACKAGING WEIGHT % ATRASENTAN TABLETCONFIGURATION INITIAL 1 MONTH 3 MONTHS 6 MONTHS Phase III tablet 20Tablets in a one 100.1% 100.4% 100.4% 100.3% (0.50 mg) ounce HDPE bottlecontaining 1.1 g of a silica desiccant Tablet in aluminum 99.3% 98.8%100.6% 99.3% (A1) foil blister Tablet in an ACLAR ® 99.9% 98.6% 99.5%97.1% 4000 blister 32 Tablets blistered in 99.4% 97.7% 100.1% 99.1% anACLAR ® 4000 blister sealed in a foil overwrap with 1.1 g of a silicadesiccant Phase IIb tablet 32 Tablets blistered in 99.3% 98.8% 100.8%99.6% (0.50 mg) an ACLAR ® Rx160 blister sealed in a foil overwrap with1.1 g of a silica desiccant Tablet in aluminum 98.8% 96.9% 95.7% 96.7%(A1) foil blister Tablet in an ACLAR ® 100.2% 97.9% 95.3% 91.2% 3000blister

With the exception of the more protective blister sealed in a foiloverwrap with desiccant packaging, the Phase III tablet containingL-cysteine exhibited improved stability relative to the Phase IIb tabletin all packaging configurations tested and should be suitable for use ina variety of blister package configurations.

Example 12 Preparation of Phase III Tablets

One batch of the 0.75 mg Phase III tablets (i.e., the tabletcorresponding to Table 10-B of Example 10) was prepared as describedbelow.

Atrasentan monohydrochloride (0.67 kg) and a first portion ofhydroxypropyl methylcellulose (Hypromellose E5, 0.84 kg) were added to apoly-bag and manually blended for about five minutes. The mixture ofatrasentan monohydrochloride/hydroxypropyl methylcellulose was addedslowly to water (9.4 kg) with stirring to form a suspension. Thesuspension was cooled to 12° C. and the cooled suspension was mixed forthree cycles under the following mixing conditions: two minutes of highshear mixing using an agitator and homogenizer at 100% of the maximumspeed followed by 120 minutes of mixing using the agitator only at 100%of the maximum speed. The suspension was mixed for an additional ninehours at 12° C. using the agitator at 100% of the maximum speed.L-cysteine hydrochloride monohydrate (0.216 kg) was added to thesuspension with stirring. The suspension was mixed for an additional 20minutes using an agitator at 100% of the maximum speed and then heatedto 20° C.

The intragranular excipients lactose monohydrate (90.61 kg), a secondportion of hydroxypropyl methylcellulose (Hypromellose E5, 2.16 kg),crospovidone (POLYPLASDONE™ XL, 3.5 kg), and a first portion of silicondioxide (SYLOID®, 0.25 kg) were added to a single pot processor andblended for 10 minutes at 10 RPM. The intragranular excipients were thenblended for an additional five minutes at 102 RPM. The atrasentansuspension prepared as described above was then added to the single potprocessor at an average rate of 3.8 kg/minute while the contents ofsingle pot processor were mixed at 102 RPM. Rinse water (7.6 kg) wasadded to the suspension vessel and the rinse water was then transferredto the single pot processor at an average rate of 3.8 kg/minutes whilethe contents of the single pot processor were mixed at 102 RPM.

The resulting granulation mixture was wet-massed with high shear mixingfor 30 seconds to one minute to an achieved target power end point (6.3kW). The granulation mixture was dried under vacuum at less than 15 mbarwith the single pot processor bowl and lid temperature maintained at 75°C. until a loss on drying moisture measurement of 0.7% to 1.8% wasachieved. The granulation mixture was milled using a COMIL® to achieve atarget particle size distribution of 250 μm (d90) and 100 μm (d50).

The extragranular excipients glycerol behenate (COMPRITOL®, 1.5 kg) anda second portion of silicon dioxide (SYLOID®, 0.25 kg) were added to thesingle pot processor and the extragranular excipients and milledgranulation mixture were blended for 10 minutes at 10 RPM. The blend wascompressed to prepare tablet cores having a weight of 120 mg and ahardness greater than or equal to 40 N. An aqueous solution containing9.7% HPMC and 0.3% Polyethylene Glycol 1450 was prepared for use as atablet coating solution. The tablet cores were coated with a sufficientamount of the coating solution to provide a 3% weight gain and a targettablet weight of 123.6 mg.

The 0.50 mg Phase III tablet (i.e., the tablet corresponding to Table10-B of Example 10) can be prepared in a similar manner to the batch ofthe 0.75 mg Phase III tablet described above with the amount ofatrasentan monohydrochloride, L-cysteine hydrochloride monohydrate, andlactose monohydrate adjusted accordingly (i.e., the amount of atrasentanmonohydrochloride used in each batch of the 0.50 mg Phase III tablets is0.449 kg).

All references (patent and non-patent) cited above are incorporated byreference into this patent application. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

We claim:
 1. A method of treating type 2 diabetes, microalbuminuria ormacroalbuminuria, the method comprising administering daily to a humansubject a dosage form comprising: (a) about 0.25 mg to about 1.25 mg ofatrasentan, or an equivalent amount of a pharmaceutically acceptablesalt thereof; wherein the weight percent of atrasentan, orpharmaceutically acceptable salt thereof, in the dosage form is fromabout 0.05 weight percent to about 2.0 weight percent on an atrasentanfree base equivalent weight basis; (b) a pharmaceutically acceptableanti-oxidant; wherein the molar ratio of the anti-oxidant to atrasentan,or pharmaceutically acceptable salt thereof, is from about 10:1 to about1:10; and (c) a pharmaceutically acceptable diluent, wherein the humansubject is susceptible to, or is suffering from, type 2 diabetes,microalbuminuria or macroalbuminuria.
 2. The method of claim 1 whereinthe anti-oxidant is L-cysteine, or a pharmaceutically acceptable salt orester thereof.
 3. The method of claim 1 wherein the weight percent ofthe anti-oxidant in the dosage form is from about 0.05 weight percent toabout 1.0 weight percent.
 4. The method of claim 1 wherein the dosageform further comprises a binder.
 5. The method of claim 4 wherein thebinder is selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose.
 6. The method of claim 4 wherein: (a) the weightto weight ratio of the binder to atrasentan, or pharmaceuticallyacceptable salt thereof, in the dosage form is from about 2:1 to about25:1 on an atrasentan free base equivalent weight basis; and (b) theweight percent of the binder in the dosage form is from about 1.0 weightpercent to about 10.0 weight percent.
 7. The method of claim 4 wherein:(a) the molar ratio of the anti-oxidant to atrasentan, orpharmaceutically acceptable salt thereof, in the dosage form is fromabout 5:1 to about 1:5; and (b) the weight to weight ratio of the binderto atrasentan, or pharmaceutically acceptable salt thereof, in thedosage form is from about 1:1 to about 20:1 on an atrasentan free baseequivalent weight basis.
 8. The method of claim 4 wherein the dosageform comprises: (a) from about 0.05 weight percent to about 1.0 weightpercent of the anti-oxidant; and (b) from about 1.0 weight percent toabout 10.0 weight percent of the binder.
 9. The method of claim 1wherein the dosage form: (a) comprises from about 0.05 weight percent toabout 1.0 weight percent of the anti-oxidant; (b) comprises from about75 weight percent to about 99 weight percent of the diluent; (c) furthercomprises from about 1.0 weight percent to about 10.0 weight percent ofa pharmaceutically acceptable binder; (d) optionally further comprisesfrom about 1.0 weight percent to about 10.0 weight percent of apharmaceutically acceptable disintegrant; (e) optionally furthercomprises from about 0 weight percent to about 1.5 weight percent of apharmaceutically acceptable glidant; and (f) optionally furthercomprises from about 0 weight percent to about 5.0 weight percent of apharmaceutically acceptable lubricant, wherein the cumulative weightpercent for all components of the dosage form equals 100 percent.
 10. Amethod of preparing a stable pharmaceutical dosage form, the methodcomprising: (a) combining atrasentan, or a pharmaceutically acceptablesalt thereof, with a pharmaceutically acceptable polymeric binder toform a first mixture; (b) blending the first mixture with apharmaceutically acceptable diluent and a pharmaceutically acceptableanti-oxidant to form a second mixture; and (c) encapsulating ortableting the second mixture to yield the dosage form, wherein the molarratio of the anti-oxidant to atrasentan, or pharmaceutically acceptablesalt thereof, is from about 10:1 to about 1:10.
 11. The method of claim10 wherein the stable pharmaceutical dosage form comprises from about0.25 mg to about 1.25 mg of atrasentan or a pharmaceutically acceptablesalt thereof.
 12. The method of claim 10 wherein the second mixturefurther comprises a disintegrant, wherein the weight to weight ratio ofthe disintegrant to the anti-oxidant is from about 60:1 to about 3:1.13. The method of claim 10 wherein the dosage form comprises: (a) fromabout 0.25 mg to about 1.25 mg of atrasentan or a pharmaceuticallyacceptable salt thereof; (b) from about 1.0 weight percent to about 10.0weight percent of the binder; (c) from about 75 weight percent to about99 weight percent of the diluent; and (d) from about 0.05 weight percentto about 1.0 weight percent of the anti-oxidant.
 14. The method of claim10 wherein the anti-oxidant is L-cysteine, or a pharmaceuticallyacceptable salt or ester thereof.
 15. The method of claim 10 wherein thebinder is selected from the group consisting ofhydroxymethylpropylcellulose, hydroxyethylpropylcellulose, andhydroxypropylcellulose.
 16. The method of claim 10 wherein the weight toweight ratio of the binder to atrasentan, or a pharmaceuticallyacceptable salt thereof, is from about 2:1 to about 25:1 on anatrasentan free base equivalent weight basis.
 17. The method of claim 10wherein: the first mixture is a solution of atrasentan and the binder ora suspension of atrasentan and the binder; the first mixture is blendedwith dry diluent and dry anti-oxidant in a wet granulation step to formthe second mixture; and the second mixture is dried prior toencapsulating or tableting.
 18. The method of claim 17 wherein a firstportion of the binder is added to the first mixture and a second portionof the binder is added to the second mixture.
 19. The method of claim 10wherein the first mixture is a dry mixture and the second mixture is adry mixture.
 20. The method of claim 19 wherein the first mixture iscompressed to form dry granules prior to blending with the diluent andthe anti-oxidant.